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Review

Emerging Roles of Ceramides in Breast Cancer Biology and Therapy

by
Purab Pal
1,
G. Ekin Atilla-Gokcumen
2,* and
Jonna Frasor
1,*
1
Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
2
Department of Chemistry, University at Buffalo, The State University of New York (SUNY), Buffalo, NY 14260, USA
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(19), 11178; https://doi.org/10.3390/ijms231911178
Submission received: 31 August 2022 / Revised: 15 September 2022 / Accepted: 20 September 2022 / Published: 23 September 2022
(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases 2.0)
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Abstract

:
One of the classic hallmarks of cancer is the imbalance between elevated cell proliferation and reduced cell death. Ceramide, a bioactive sphingolipid that can regulate this balance, has long been implicated in cancer. While the effects of ceramide on cell death and therapeutic efficacy are well established, emerging evidence indicates that ceramide turnover to downstream sphingolipids, such as sphingomyelin, hexosylceramides, sphingosine-1-phosphate, and ceramide-1-phosphate, is equally important in driving pro-tumorigenic phenotypes, such as proliferation, survival, migration, stemness, and therapy resistance. The complex and dynamic sphingolipid network has been extensively studied in several cancers, including breast cancer, to find key sphingolipidomic alterations that can be exploited to develop new therapeutic strategies to improve patient outcomes. Here, we review how the current literature shapes our understanding of how ceramide synthesis and turnover are altered in breast cancer and how these changes offer potential strategies to improve breast cancer therapy.

Graphical Abstract

1. Introduction

With an estimated 287,850 new cases in 2022, breast cancer (BC) is the most common cancer in women (15% of all new cancer cases) [1]. The mortality in BC patients has decreased steadily over the last twenty years from 26.6% to 19.4% [1], which can be largely attributed to improved therapeutic strategies that have come from continuous progress in understanding breast tumor biology. Therefore, the identification and characterization of important molecular targets driving BC development and progression are essential to improve the therapeutic efficacies of existing treatments, as well as to develop new therapeutic strategies.
Over the past few decades, ceramide, a bioactive sphingolipid, has emerged as an important player in several cancers, including BC, due to its critical role in regulating both cell death and cell survival. In brief, intracellular accumulation of ceramides can induce cell death, while ceramides also serve as a substrate for the production of other sphingolipids that can promote cell survival and proliferation. Therefore, tumor cells tend to employ mechanisms to restrain ceramide levels while increasing the production of ceramide’s downstream sphingolipids to support growth. In contrast, BC treatment modalities can target the sphingolipid pathway to increase ceramide levels and ceramide-mediated cell death. Since ceramide is the common precursor of downstream pro-proliferative sphingolipids, it is important to have a global perspective of ceramide metabolism, both its synthesis and turnover, for a comprehensive evaluation of its role in BC [2,3,4,5].
In this review, we will highlight new developments over the last five years in (i) the role of ceramides in BC biology, (ii) the mechanisms by which ceramide levels are regulated in BC, and (iii) the therapeutic implications of ceramide production and metabolism in BC.

2. Ceramides: Structure and Production

Ceramides are structurally defined as a sphingoid base, typically sphingosine with 18 carbons (d18), attached to a fatty acyl chain of variable length (14 to 26 carbons), the most common one being 16 carbons in mammalian cells (Figure 1) [6]. This characteristic amide group and the waxy nature of the molecules (‘cer’ meaning wax in Latin) give them the name ceramides. High hydrophobicity makes these molecules poorly water-soluble; therefore, they primarily exist in biological membranes. Ceramides are highly abundant in the outermost layer of our skin, making up about 30–40% of our epidermis and serving as a permeability barrier [7]. Intracellularly, ceramides are found in the plasma membrane, nuclear and mitochondrial envelope, endoplasmic reticulum (ER) and Golgi apparatus, where they carry out distinct functions. While ceramides in the plasma membrane serve in lipid rafts regulating membrane dynamics, ceramide accumulation in mitochondria induces apoptosis, and ceramides in the ER and Golgi are used as precursors to other sphingolipids [8].
Ceramides can be generated through de novo synthesis from the condensation of serine and a palmitoyl CoA at the ER by the enzyme serine-palmitoyl transferase (SPT). The product of this reaction is 3-keto dihydrosphingosine, which is reduced to dihydrosphingosine. Dihydrosphingosine is acylated by ceramide synthase (CERS) to yield dihydroceramide. Mammalian ceramide synthases are comprised of six isoforms, CERS1–6, which have substrate preferences based on acyl chain length. Dihydroceramides are then saturated by delta 4-desaturase (DEGS1/2) to produce ceramides. Ceramides can then be transported to the Golgi apparatus and be converted to downstream sphingolipids, which can also be converted back into ceramides and broken down through the sphingomyelinase and salvage pathways (Figure 2).

3. Canonical Role of Ceramides in BC: A Bona Fide Inducer of Cell Death

The role of ceramides in inducing apoptosis in different cancer cells, including BC, has been established by several lines of evidence. (i) Apoptosis-inducing agents increase intracellular ceramide levels prior to the initiation of the apoptotic cascade [9,10,11,12,13,14,15,16,17,18,19,20,21]. (ii) Intracellular delivery of ceramides and ceramide-analogs induces apoptosis [22,23,24,25,26]. (iii) Increasing endogenous ceramide levels trigger growth arrest and apoptosis [27,28,29,30,31,32]. Additionally, (iv) cell lines incapable of generating ceramides are resistant to chemo- and radiotherapy [17,22,27,33].
The current dogma about the mechanism by which ceramides induce apoptosis states that ceramides can form pores in the mitochondrial outer membrane (OMM), owing to their ability to form channels in planar phospholipid membranes [34]. Ceramide-induced pores in OMM result in an increased OMM permeability and a consequential release of cytochrome c and other mitochondrial proteins, such as SMAC/DIABLO, heat-shock proteins, and endonucleases, into the cytosol, thereby initiating the apoptotic cascade [35,36]. Consistent with this theory, reports show that OMM has very low ceramides and is enriched with dihydroceramides in healthy conditions. Dihydroceramides lack pore-forming ability due to their lack of a 4,5-trans bond as compared to their ceramide counterparts [37,38]. A recent report by Agnes De Mario and colleagues has suggested additional regulators that may control ceramide action in apoptosis. Ceramide-induced apoptosis in BC can be dependent on mitochondrial Ca2+ levels as an inhibitor of mitochondrial calcium uniporter (MCU), reducing mitochondrial Ca2+ uptake and decreasing Ca2+ load in the mitochondria, protecting BC cells from ceramide-induced apoptosis [39].
The fatty acyl chain length of ceramides can also be a critical factor in the molecular actions of ceramides. Several studies have described how short-chain and long-chain ceramides can have different biophysical properties that can affect their actions [40,41]. Increasing short-chain ceramides in breast cancer cells have been reported to reduce proliferation through inhibition of mTOR signaling in a recent study by Kim et al. [42]. In their study, overexpression of CERS6, which produces C14:0, C16:0, and C18:0 ceramides, but not other isoforms, resulted in inhibition of mTOR signaling and reduced cell proliferation in MCF-7 cells [42]. On the other hand, decreased levels of very long-chain ceramides (C20:0, C22:0, C24:0, and C26:0) have been reported to enhance proliferation and migration in luminal B breast tumors. Pani et al. reported that luminal B tumors have an alternate spliced (exon 8 skipped) CERS2 gene, which is associated with a poor prognosis of luminal B tumors [43]. The exon 8 corresponds to a segment in the catalytic domain of CERS2; hence, the alternate spliced variant becomes unable to synthesize long-chain ceramides, and the reduction of these ceramides promotes luminal B tumor growth. These findings suggest that more aggressive cancers are likely to employ regulatory mechanisms to restrain very long-chain ceramide generation from supporting cell proliferation and evading cell death.
Ceramide-mediated actions appear to be at the cornerstone of inducing apoptosis in BC cells. Over the last few years, several small molecules (such as fatostatin, hydroxytriolene, zoledronic acid, salvianolic acid, thymoquinone, etc.) have been described that promote cell death in BC cells through very different mechanisms [44,45,46,47,48]. For example, fatostatin induces ER-stress [44], and hydroxytriolene interacts with the plasma membrane, regulating its structure and composition, which reduces Akt signaling [45]. However, both of these small molecule inhibitors induce cell death by increasing the intracellular ceramide levels, albeit the detailed molecular underpinnings of how they increase ceramide levels have yet to be fully elucidated.

4. The Other Role of Ceramides: Conversion to Pro-Survival Sphingolipids

Ceramide, once transported to the Golgi apparatus, can also serve as a precursor to bioactive sphingolipids such as ceramide-1-phosphate (C1P) and sphingosine-1-phosphate (S1P), which can counteract the pro-apoptotic ceramide actions, or other sphingolipids such as sphingomyelin (SM) and hexosylceramide (HexCers) that are involved in cell survival, proliferation, and drug resistance (Figure 2). Ceramide conversion to other sphingolipids offers a plausible explanation for the detection of high ceramides in breast tumors from patients, as SM and S1P levels are also elevated in breast tumors [49,50,51,52,53]. Since ceramides are the precursors to produce the downstream sphingolipids, both ceramide de novo synthesis and ceramide turnover are increased in the breast tumor cells, as marked by increased gene expression of CERS2, -4, and -6, ceramide kinase (CERK), sphingosine kinase 1 (SPHK1), UDP-glucose ceramide glucosyltransferase (UGCG), and sphingomyelin synthase 1 (SGMS1), enzymes that are involved in ceramide turnover [49,53,54] (Table 1). Each of the downstream sphingolipids exerts a specific cellular function that can contribute to cell proliferation, metastasis, cancer stem cells, and drug resistance in different ways. Several studies in the past few years have improved our understanding of the cellular effects of ceramide turnover on different sphingolipids and may offer new targets for BC therapy.

4.1. Sphingosine-1-Phosphate (S1P)

Ceramide is converted to sphingosine by the action of ceramidases (CDase). Sphingosine is then phosphorylated by sphingosine kinase (SPHK1/2) to produce sphingosine-1-phosphate (S1P) [75]. S1P is secreted outside the cell, binds to S1P receptors (S1PR) and promotes cell proliferation and survival through activation of Akt and Erk-1/2 pathways [61,85]. Out of the five S1PR isoforms in humans, S1PR-1, -3, and -4 have been implicated in BC [86]. A recent study by Chen and colleagues has suggested that S1P can promote epithelial-mesenchymal transition (EMT) as well as stemness in BC cells [87]. S1P can also increase ceramide production and turnover in BC cells by increasing CERS1, -2, -6, and UGCG gene expression [88].
Three possible strategies to counter S1P’s ability to promote cell proliferation and survival have been tested in BC: (i) inhibition of CDase, (ii) inhibition of SPHK1/2 to prevent S1P production, and (iii) inhibition of S1P signaling. An inhibitor of CDase, D-erythro-MAPP treatment has been reported to increase intracellular ceramides and attenuate S1P generation, which induced cell death in MCF-7 cells (Table 1) [73]. Similarly, several small molecule inhibitors of SPHK1/2 and S1PR have been shown to inhibit BC cell growth both in vitro and in vivo [75,76,77,78,79,80], of which FTY720 (fingolimod, an FDA-approved drug for multiple sclerosis), has been extensively studied. FTY720 is a prodrug, which upon phosphorylation by SPHK2, yields phospho-FTY720, which acts as an antagonist for S1PR1, thereby inhibiting BC cell survival and proliferation [86]. Additionally, FTY720 has also been reported to potentiate the chemotherapeutic efficacy of docetaxel and doxorubicin in BC cells in two recent studies [81,82], thereby suggesting that attenuation of S1P generation or signaling can be a potential therapeutic strategy for the treatment of BC.

4.2. Ceramide-1-Phosphate (C1P)

Ceramide kinase (CERK) phosphorylates ceramides to produce ceramide-1-phosphate (C1P), another bioactive signaling sphingolipid involved in pro-survival and pro-proliferative actions. Recently, two studies have elucidated the molecular actions of C1P in BC, which suggested that cellular actions of C1P are mediated by the production of C-C Motif Chemokine Ligand 5 (CCL5) [89] and activation of PI3K and Akt pathways [90]. An increasing body of evidence has implicated C1P in cell migration and metastasis in BC [61,62,63]. A recent study that reported an increased CERK expression in the lung and bone metastatic cells of an MDA-MB-231 tumor supports the role of C1P in metastasis [90]. Along this line, CERK expression has been shown to be associated with a worse prognosis in TNBC patients [64]. A recent report by Zhu and colleagues has shown that overexpression of CERK in TNBC cells promotes cell growth, migration, and chemoresistance [65,66]. Interestingly, C1P also plays an important role in endocrine therapy-resistant cell survival, as inhibition of CERK induces cell death in therapy-resistant BC cells via loss of C1P [91]. Owing to C1P’s ability to inhibit de novo ceramide production, CERK inhibition can induce ceramide accumulation and consequent cell death in endocrine therapy-resistant BC cells [91,92].
Of note, high levels of very long odd-carbon chain C1P (C23:0 C1P and C23:1 C1P) have been detected in breast tumors from patients compared to the tumor-adjacent normal tissue [49], and C1P levels are also positively correlated with Ki-67 index of the breast tumors [49], suggesting that C1P level can be a potential prognostic parameter in breast cancer patients [93].

4.3. Sphingomyelins (SM)

Sphingomyelins (SM) are essential components of biological membranes; therefore, they are necessary for cell growth and proliferation. SM are generated from ceramides by the action of sphingomyelin synthase (SGMS-1/2). A recent report has implicated SM in BC metastasis and aggressiveness. Their findings suggest that SGMS2 promotes EMT through activation of the TGF-ß/SMAD pathway, more specifically, by increasing TGF-ß1 secretion [83]. An increase in ceramide turnover to SM is also an important feature of chemotherapy resistance in BC [84].

4.4. Hexosylceramides (HexCer)

From a wider perspective of overall cancers, the sphingolipids that play an important role in therapy resistance are undoubtedly the hexosylceramides (HexCer), a group of ceramide metabolites that have a neutral sugar moiety linked to a ceramide [94]. They serve as precursors to complex glycosphingolipids like globosides and gangliosides. The enzyme that converts ceramides to glucosylceramides, UDP-glucose ceramide glucosyltransferase (UGCG), is upregulated in multidrug resistance in multiple cancers [94,95]. In BC, UGCG has been reported to upregulate multidrug resistance protein 1 (MDR1), which confers drug resistance by acting as a drug-efflux pump, thereby keeping the intracellular drug concentration low [54]. An in vitro study has shown that co-suppression of MDR1 and UGCG can increase sensitivity to chemotherapeutic drugs in BC cells [96].
Glucosylceramides also play a crucial role in the metabolic reprogramming of breast cancer. Overexpression of UGCG increases glutamine synthesis and metabolism in BC, a common feature of therapy-resistant BC [67,68,69]. UGCG also confers additional metabolic changes which favor energy metabolism of therapy-resistance BC cells [70,71]. UGCG overexpression increases both glycolysis, oxidative phosphorylation, and amino acid synthesis in breast cancer cells [69,72]. In addition to metabolic changes, UGCG can also induce critical changes in the plasma membrane. Increasing glycosphingolipid and globotriacylceramide levels in the glycosphingolipid-enriched microdomains impacts multiple cellular signaling pathways in cell proliferation and drug resistance [97].

5. Therapeutic Implications of Ceramides in Breast Cancer

Treatment of BC involves multiple strategies, often depending on the molecular subtype and the size and spread of the tumor. While endocrine therapy (ET) (aromatase inhibitors or antiestrogens such as tamoxifen) is the standard of care for most hormone receptor-positive tumors, chemotherapy is the most common neoadjuvant therapeutic approach for other molecular types [98]. Depending on the presence of cancer cells in the sentinel node, radiotherapy is also often employed as a treatment modality [99]. Accumulation of ceramides has been reported as a result of ET, chemo- and radiotherapy, suggesting that ceramide-mediated cell death is an essential feature of neoadjuvant therapies, although ceramide accumulation occurs through different mechanisms. Tamoxifen treatment induces ceramide accumulation and consequent cell death in MCF-7 and MDA-MB-231 cells through the inhibition of acid ceramidase (aCDase) [58,59,100]. Tamoxifen-mediated inhibition of aCDase and the subsequent increase in ceramides and loss of S1P are thought to occur in an estrogen receptor-independent manner, suggesting tamoxifen may have some efficacy in in triple negative breast cancer, as well as other cancer types [101].
In contrast to ET, ionizing radiation relies on acid sphingomyelinase (aSMase) activity to induce ceramide accumulation and cell death in BC cells [57,60]. This was supported by a study where aSMase-null lymphoblasts were shown to be insensitive to radiation therapy and to be re-sensitized upon aSMase overexpression [102]. Similar to radiotherapy, cellular actions of chemotherapeutic agents, such as paclitaxel, also involve aSMase-mediated ceramide generation and subsequent cell death in BC cells [103]. Additionally, another study has reported that paclitaxel can also increase de novo ceramide production through activating SPT in breast tumors [55], suggesting that chemotherapeutic agents may promote intracellular ceramide accumulation through a combination of increasing de novo ceramide production and breakdown of downstream sphingolipids.
Considering the role of ceramides in cell death and the role of ceramide downstream metabolites in cell proliferation and survival, it is plausible that therapy-resistant cells take certain measures to keep their ceramide levels regulated. Recently, Shammout and colleagues compared doxorubicin-sensitive and -resistant MCF-7 cells and found that the doxorubicin-resistant cells maintain an increased level of SM and decreased levels of ceramides, dihydroceramides, and HexCers [84]. Similarly, our profiling study of tamoxifen-sensitive and -resistant cells also found decreased ceramide and HexCers levels in tamoxifen-resistant cells, although SM and dihydroceramide levels were found to be unaltered [91]. The different sphingolipidomic changes employed by different therapy-resistant cells to maintain lower ceramide levels need to be validated in preclinical models and patient tumors. Additionally, ceramide downregulation also requires to be mechanistically elucidated for devising new therapeutic strategies and improving patient outcomes.
The majority of the ceramide-based therapeutics in BC are in preclinical or clinical I/II phases and are mostly focused on preventing ceramide turnover to downstream sphingolipids (Table 2). Few studies that have attempted to deliver ceramides to tumor cells to induce cell death have used synthetic short-chain ceramides formulated in nanoliposomes for an efficacious intracellular delivery. Ceramide nanoliposomes (CNL) have inhibited cell proliferation and migration in TNBC cells [58,104,105]. Of note, one study has employed a topical application of C2 and C6 CNL in a phase II study against cutaneous breast cancer patients. While the formulation of C2 and C6 CNL showed no toxicity in patients, only 4% responded to the treatment [106]. Although this low response rate in patients suspended further clinical trials with CNL, adding short-chain ceramides in nanoliposome-based formulations has been studied to increase the chemotherapeutic efficacies BC drugs [107,108,109]. Of note, C12-ceramide-containing liposomes have improved cellular targeting and synergized with the therapeutic efficacy of docetaxel and doxorubicin in BC cells in a recent study [110].

6. Concluding Remarks

Ceramides have become increasingly relevant in BC with a growing understanding of the different regulatory mechanisms of ceramide production and turnover employed by the cancer cells to promote different hallmarks of cancer. The understanding of the regulatory network has also been essential for the development of new therapeutic strategies for BC patients. Several ceramide-based cancer therapeutics are currently being tested in preclinical and clinical (phase I and II) trials for BC, either alone or in combination with other neoadjuvant therapies [138].
Of note, sphingolipidomic profiling studies of therapy-sensitive and -resistant tumors have opened the possibility of ceramide-based treatment modalities in therapy-resistant breast tumors. In both chemotherapy and endocrine therapy-resistant BC cells, maintaining low ceramide levels has been observed as a common feature of therapy resistance. However, these observations are yet to be validated in patient-derived xenografts (PDX) or patient tumors. Further evidence and more mechanistic knowledge about this altered ceramide regulation can potentially be leveraged into an improved therapeutic application for patients with therapy-resistant disease.
There are several pertinent questions that remain to be addressed. For example, the genetic determinants for altered ceramide regulation are largely unresolved. Apart from a recent study showing alternative splicing of CERS2 in luminal B tumors, genetic signatures for altered ceramide regulation are not well-elucidated. Additionally, the cellular and molecular determinants for ceramide sensitivity are also somewhat obscure. As a bioactive lipid, ceramide can interact with other proteins, and these interactions in BC need to be characterized. Future studies elucidating these mechanisms will offer novel and improved strategies and a new frontier of BC therapeutics.

Author Contributions

Conceptualization, P.P., G.E.A.-G. and J.F.; writing—original draft preparation, P.P.; writing—review and editing, G.E.A.-G. and J.F.; funding acquisition, G.E.A.-G. and J.F. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Department of Defense (DoD) grant numbers W81XWH-20-1-0486 (J.F.) and W81XWH-20-1-0487 (G.E.A.-G.).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. National Cancer Institute (NCI) Surveillance; End Results Program. Cancer Stat Facts: Female Breast Cancer; National Cancer Institute (NCI): Bethesda, MD, USA, 2021.
  2. Espaillat, M.P.; Shamseddine, A.A.; Adada, M.M.; Hannun, Y.A.; Obeid, L.M. Ceramide and sphingosine-1-phosphate in cancer, two faces of the sphinx. Transl. Cancer Res. 2015, 4, 484–499. [Google Scholar]
  3. Sheridan, M.; Ogretmen, B. The Role of Ceramide Metabolism and Signaling in the Regulation of Mitophagy and Cancer Therapy. Cancers 2021, 13, 2475. [Google Scholar] [CrossRef] [PubMed]
  4. Moro, K.; Nagahashi, M.; Gabriel, E.; Takabe, K.; Wakai, T. Clinical application of ceramide in cancer treatment. Breast Cancer 2019, 26, 407–415. [Google Scholar] [CrossRef] [PubMed]
  5. Mashhadi Akbar Boojar, M.; Mashhadi Akbar Boojar, M.; Golmohammad, S. Ceramide pathway: A novel approach to cancer chemotherapy. Egypt. J. Basic Appl. Sci. 2018, 5, 237–244. [Google Scholar] [CrossRef]
  6. Fahy, E.; Subramaniam, S.; Brown, H.A.; Glass, C.K.; Merrill, A.H., Jr.; Murphy, R.C.; Raetz, C.R.; Russell, D.W.; Seyama, Y.; Shaw, W.; et al. A comprehensive classification system for lipids. J. Lipid. Res. 2005, 46, 839–861. [Google Scholar] [CrossRef]
  7. Goni, F.M.; Contreras, F.X.; Montes, L.R.; Sot, J.; Alonso, A. Biophysics (and sociology) of ceramides. Biochem. Soc. Symp. 2005, 72, 177–188. [Google Scholar] [CrossRef]
  8. Vielhaber, G.; Pfeiffer, S.; Brade, L.; Lindner, B.; Goldmann, T.; Vollmer, E.; Hintze, U.; Wittern, K.P.; Wepf, R. Localization of ceramide and glucosylceramide in human epidermis by immunogold electron microscopy. J. Investig. Derm. 2001, 117, 1126–1136. [Google Scholar] [CrossRef]
  9. Obeid, L.M.; Linardic, C.M.; Karolak, L.A.; Hannun, Y.A. Programmed cell death induced by ceramide. Science 1993, 259, 1769–1771. [Google Scholar] [CrossRef]
  10. Modur, V.; Zimmerman, G.A.; Prescott, S.M.; McIntyre, T.M. Endothelial cell inflammatory responses to tumor necrosis factor alpha. Ceramide-dependent and -independent mitogen-activated protein kinase cascades. J. Biol. Chem. 1996, 271, 13094–13102. [Google Scholar] [CrossRef]
  11. Garcia-Ruiz, C.; Colell, A.; Mari, M.; Morales, A.; Fernandez-Checa, J.C. Direct effect of ceramide on the mitochondrial electron transport chain leads to generation of reactive oxygen species. Role of mitochondrial glutathione. J. Biol. Chem. 1997, 272, 11369–11377. [Google Scholar] [CrossRef]
  12. Geilen, C.C.; Bektas, M.; Wieder, T.; Kodelja, V.; Goerdt, S.; Orfanos, C.E. 1alpha,25-dihydroxyvitamin D3 induces sphingomyelin hydrolysis in HaCaT cells via tumor necrosis factor alpha. J. Biol. Chem. 1997, 272, 8997–9001. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Sawada, M.; Nakashima, S.; Banno, Y.; Yamakawa, H.; Hayashi, K.; Takenaka, K.; Nishimura, Y.; Sakai, N.; Nozawa, Y. Ordering of ceramide formation, caspase activation, and Bax/Bcl-2 expression during etoposide-induced apoptosis in C6 glioma cells. Cell Death Differ. 2000, 7, 761–772. [Google Scholar] [CrossRef] [PubMed]
  14. Wiesner, D.A.; Dawson, G. Staurosporine induces programmed cell death in embryonic neurons and activation of the ceramide pathway. J. Neurochem. 1996, 66, 1418–1425. [Google Scholar] [CrossRef] [PubMed]
  15. Come, M.G.; Bettaieb, A.; Skladanowski, A.; Larsen, A.K.; Laurent, G. Alteration of the daunorubicin-triggered sphingomyelin-ceramide pathway and apoptosis in MDR cells: Influence of drug transport abnormalities. Int. J. Cancer 1999, 81, 580–587. [Google Scholar] [CrossRef]
  16. Cifone, M.G.; Migliorati, G.; Parroni, R.; Marchetti, C.; Millimaggi, D.; Santoni, A.; Riccardi, C. Dexamethasone-induced thymocyte apoptosis: Apoptotic signal involves the sequential activation of phosphoinositide-specific phospholipase C, acidic sphingomyelinase, and caspases. Blood 1999, 93, 2282–2296. [Google Scholar] [CrossRef]
  17. Alphonse, G.; Aloy, M.T.; Broquet, P.; Gerard, J.P.; Louisot, P.; Rousson, R.; Rodriguez-Lafrasse, C. Ceramide induces activation of the mitochondrial/caspases pathway in Jurkat and SCC61 cells sensitive to gamma-radiation but activation of this sequence is defective in radioresistant SQ20B cells. Int. J. Radiat. Biol. 2002, 78, 821–835. [Google Scholar] [CrossRef]
  18. Vit, J.P.; Rosselli, F. Role of the ceramide-signaling pathways in ionizing radiation-induced apoptosis. Oncogene 2003, 22, 8645–8652. [Google Scholar] [CrossRef]
  19. Takeda, Y.; Tashima, M.; Takahashi, A.; Uchiyama, T.; Okazaki, T. Ceramide generation in nitric oxide-induced apoptosis. Activation of magnesium-dependent neutral sphingomyelinase via caspase-3. J. Biol. Chem. 1999, 274, 10654–10660. [Google Scholar] [CrossRef]
  20. Masamune, A.; Igarashi, Y.; Hakomori, S. Regulatory role of ceramide in interleukin (IL)-1 beta-induced E-selectin expression in human umbilical vein endothelial cells. Ceramide enhances IL-1 beta action, but is not sufficient for E-selectin expression. J. Biol. Chem. 1996, 271, 9368–9375. [Google Scholar] [CrossRef]
  21. Birbes, H.; El Bawab, S.; Obeid, L.M.; Hannun, Y.A. Mitochondria and ceramide: Intertwined roles in regulation of apoptosis. Adv. Enzym. Regul. 2002, 42, 113–129. [Google Scholar] [CrossRef]
  22. Sautin, Y.; Takamura, N.; Shklyaev, S.; Nagayama, Y.; Ohtsuru, A.; Namba, H.; Yamashita, S. Ceramide-induced apoptosis of human thyroid cancer cells resistant to apoptosis by irradiation. Thyroid 2000, 10, 733–740. [Google Scholar] [CrossRef] [PubMed]
  23. Lozano, J.; Menendez, S.; Morales, A.; Ehleiter, D.; Liao, W.C.; Wagman, R.; Haimovitz-Friedman, A.; Fuks, Z.; Kolesnick, R. Cell autonomous apoptosis defects in acid sphingomyelinase knockout fibroblasts. J. Biol. Chem. 2001, 276, 442–448. [Google Scholar] [CrossRef] [PubMed]
  24. Selzner, M.; Bielawska, A.; Morse, M.A.; Rudiger, H.A.; Sindram, D.; Hannun, Y.A.; Clavien, P.A. Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer. Cancer Res. 2001, 61, 1233–1240. [Google Scholar] [PubMed]
  25. Kimura, K.; Markowski, M.; Edsall, L.C.; Spiegel, S.; Gelmann, E.P. Role of ceramide in mediating apoptosis of irradiated LNCaP prostate cancer cells. Cell Death Differ. 2003, 10, 240–248. [Google Scholar] [CrossRef]
  26. Morstein, J.; Kol, M.; Novak, A.J.E.; Feng, S.; Khayyo, S.; Hinnah, K.; Li-Purcell, N.; Pan, G.; Williams, B.M.; Riezman, H.; et al. Short Photoswitchable Ceramides Enable Optical Control of Apoptosis. ACS Chem. Biol. 2021, 16, 452–456. [Google Scholar] [CrossRef]
  27. Chmura, S.J.; Mauceri, H.J.; Advani, S.; Heimann, R.; Beckett, M.A.; Nodzenski, E.; Quintans, J.; Kufe, D.W.; Weichselbaum, R.R. Decreasing the apoptotic threshold of tumor cells through protein kinase C inhibition and sphingomyelinase activation increases tumor killing by ionizing radiation. Cancer Res. 1997, 57, 4340–4347. [Google Scholar]
  28. Alphonse, G.; Bionda, C.; Aloy, M.T.; Ardail, D.; Rousson, R.; Rodriguez-Lafrasse, C. Overcoming resistance to gamma-rays in squamous carcinoma cells by poly-drug elevation of ceramide levels. Oncogene 2004, 23, 2703–2715. [Google Scholar] [CrossRef]
  29. Rodriguez-Lafrasse, C.; Alphonse, G.; Aloy, M.T.; Ardail, D.; Gerard, J.P.; Louisot, P.; Rousson, R. Increasing endogenous ceramide using inhibitors of sphingolipid metabolism maximizes ionizing radiation-induced mitochondrial injury and apoptotic cell killing. Int. J. Cancer 2002, 101, 589–598. [Google Scholar] [CrossRef]
  30. Raisova, M.; Goltz, G.; Bektas, M.; Bielawska, A.; Riebeling, C.; Hossini, A.M.; Eberle, J.; Hannun, Y.A.; Orfanos, C.E.; Geilen, C.C. Bcl-2 overexpression prevents apoptosis induced by ceramidase inhibitors in malignant melanoma and HaCaT keratinocytes. FEBS Lett. 2002, 516, 47–52. [Google Scholar] [CrossRef]
  31. Wang, S.; Su, X.; Xu, M.; Xiao, X.; Li, X.; Li, H.; Keating, A.; Zhao, R.C. Exosomes secreted by mesenchymal stromal/stem cell-derived adipocytes promote breast cancer cell growth via activation of Hippo signaling pathway. Stem. Cell Res. 2019, 10, 117. [Google Scholar] [CrossRef]
  32. Cheng, Q.; Li, X.; Wang, Y.; Dong, M.; Zhan, F.H.; Liu, J. The ceramide pathway is involved in the survival, apoptosis and exosome functions of human multiple myeloma cells in vitro. Acta Pharm. Sin. 2018, 39, 561–568. [Google Scholar] [CrossRef] [PubMed]
  33. Bruno, A.P.; Laurent, G.; Averbeck, D.; Demur, C.; Bonnet, J.; Bettaieb, A.; Levade, T.; Jaffrezou, J.P. Lack of ceramide generation in TF-1 human myeloid leukemic cells resistant to ionizing radiation. Cell Death Differ. 1998, 5, 172–182. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Pettus, B.J.; Chalfant, C.E.; Hannun, Y.A. Ceramide in apoptosis: An overview and current perspectives. Biochim. Biophys. Acta 2002, 1585, 114–125. [Google Scholar] [CrossRef]
  35. Siskind, L.J.; Kolesnick, R.N.; Colombini, M. Ceramide channels increase the permeability of the mitochondrial outer membrane to small proteins. J. Biol. Chem. 2002, 277, 26796–26803. [Google Scholar] [CrossRef]
  36. Di Paola, M.; Zaccagnino, P.; Montedoro, G.; Cocco, T.; Lorusso, M. Ceramide induces release of pro-apoptotic proteins from mitochondria by either a Ca2+-dependent or a Ca2+-independent mechanism. J. Bioenergy Biomembr. 2004, 36, 165–170. [Google Scholar] [CrossRef]
  37. Siskind, L.J.; Colombini, M. The lipids C2- and C16-ceramide form large stable channels. Implications for apoptosis. J. Biol. Chem. 2000, 275, 38640–38644. [Google Scholar] [CrossRef]
  38. Contreras, F.X.; Basanez, G.; Alonso, A.; Herrmann, A.; Goni, F.M. Asymmetric addition of ceramides but not dihydroceramides promotes transbilayer (flip-flop) lipid motion in membranes. Biophys. J. 2005, 88, 348–359. [Google Scholar] [CrossRef]
  39. De Mario, A.; Tosatto, A.; Hill, J.M.; Kriston-Vizi, J.; Ketteler, R.; Vecellio Reane, D.; Cortopassi, G.; Szabadkai, G.; Rizzuto, R.; Mammucari, C. Identification and functional validation of FDA-approved positive and negative modulators of the mitochondrial calcium uniporter. Cell Rep. 2021, 35, 109275. [Google Scholar] [CrossRef]
  40. Sot, J.; Aranda, F.J.; Collado, M.I.; Goni, F.M.; Alonso, A. Different effects of long- and short-chain ceramides on the gel-fluid and lamellar-hexagonal transitions of phospholipids: A calorimetric, NMR, and x-ray diffraction study. Biophys. J. 2005, 88, 3368–3380. [Google Scholar] [CrossRef]
  41. Sot, J.; Goni, F.M.; Alonso, A. Molecular associations and surface-active properties of short- and long-N-acyl chain ceramides. Biochim. Biophys. Acta 2005, 1711, 12–19. [Google Scholar] [CrossRef]
  42. Kim, M.H.; Park, J.W.; Lee, E.J.; Kim, S.; Shin, S.H.; Ahn, J.H.; Jung, Y.; Park, I.; Park, W.J. C16-ceramide and sphingosine 1-phosphate/S1PR2 have opposite effects on cell growth through mTOR signaling pathway regulation. Oncol. Rep. 2018, 40, 2977–2987. [Google Scholar] [CrossRef] [PubMed]
  43. Pani, T.; Rajput, K.; Kar, A.; Sharma, H.; Basak, R.; Medatwal, N.; Saha, S.; Dev, G.; Kumar, S.; Gupta, S.; et al. Alternative splicing of ceramide synthase 2 alters levels of specific ceramides and modulates cancer cell proliferation and migration in Luminal B breast cancer subtype. Cell Death Dis. 2021, 12, 171. [Google Scholar] [CrossRef]
  44. Brovkovych, V.; Izhar, Y.; Danes, J.M.; Dubrovskyi, O.; Sakallioglu, I.T.; Morrow, L.M.; Atilla-Gokcumen, G.E.; Frasor, J. Fatostatin induces pro- and anti-apoptotic lipid accumulation in breast cancer. Oncogenesis 2018, 7, 66. [Google Scholar] [CrossRef] [PubMed]
  45. Guardiola-Serrano, F.; Beteta-Gobel, R.; Rodriguez-Lorca, R.; Ibarguren, M.; Lopez, D.J.; Teres, S.; Alonso-Sande, M.; Higuera, M.; Torres, M.; Busquets, X.; et al. The triacylglycerol, hydroxytriolein, inhibits triple negative mammary breast cancer cell proliferation through a mechanism dependent on dihydroceramide and Akt. Oncotarget 2019, 10, 2486–2507. [Google Scholar] [CrossRef] [PubMed]
  46. Sha, W.; Zhou, Y.; Ling, Z.Q.; Xie, G.; Pang, X.; Wang, P.; Gu, X. Antitumor properties of Salvianolic acid B against triple-negative and hormone receptor-positive breast cancer cells via ceramide-mediated apoptosis. Oncotarget 2018, 9, 36331–36343. [Google Scholar] [CrossRef]
  47. Aslan, M.; Afsar, E.; Kirimlioglu, E.; Ceker, T.; Yilmaz, C. Antiproliferative Effects of Thymoquinone in MCF-7 Breast and HepG2 Liver Cancer Cells: Possible Role of Ceramide and ER Stress. Nutr. Cancer 2021, 73, 460–472. [Google Scholar] [CrossRef]
  48. Cao, Q.; Chen, X.; Wu, X.; Liao, R.; Huang, P.; Tan, Y.; Wang, L.; Ren, G.; Huang, J.; Dong, C. Inhibition of UGT8 suppresses basal-like breast cancer progression by attenuating sulfatide-alphaVbeta5 axis. J. Exp. Med. 2018, 215, 1679–1692. [Google Scholar] [CrossRef]
  49. Bhadwal, P.; Dahiya, D.; Shinde, D.; Vaiphei, K.; Math, R.G.H.; Randhawa, V.; Agnihotri, N. LC-HRMS based approach to identify novel sphingolipid biomarkers in breast cancer patients. Sci. Rep. 2020, 10, 4668. [Google Scholar] [CrossRef]
  50. Moro, K.; Kawaguchi, T.; Tsuchida, J.; Gabriel, E.; Qi, Q.; Yan, L.; Wakai, T.; Takabe, K.; Nagahashi, M. Ceramide species are elevated in human breast cancer and are associated with less aggressiveness. Oncotarget 2018, 9, 19874–19890. [Google Scholar] [CrossRef]
  51. Nagahashi, M.; Tsuchida, J.; Moro, K.; Hasegawa, M.; Tatsuda, K.; Woelfel, I.A.; Takabe, K.; Wakai, T. High levels of sphingolipids in human breast cancer. J. Surg. Res. 2016, 204, 435–444. [Google Scholar] [CrossRef]
  52. Schiffmann, S.; Sandner, J.; Birod, K.; Wobst, I.; Angioni, C.; Ruckhaberle, E.; Kaufmann, M.; Ackermann, H.; Lotsch, J.; Schmidt, H.; et al. Ceramide synthases and ceramide levels are increased in breast cancer tissue. Carcinogenesis 2009, 30, 745–752. [Google Scholar] [CrossRef] [PubMed]
  53. Erez-Roman, R.; Pienik, R.; Futerman, A.H. Increased ceramide synthase 2 and 6 mRNA levels in breast cancer tissues and correlation with sphingosine kinase expression. Biochem. Biophys. Res. Commun. 2010, 391, 219–223. [Google Scholar] [CrossRef] [PubMed]
  54. Liu, Y.Y.; Gupta, V.; Patwardhan, G.A.; Bhinge, K.; Zhao, Y.; Bao, J.; Mehendale, H.; Cabot, M.C.; Li, Y.T.; Jazwinski, S.M. Glucosylceramide synthase upregulates MDR1 expression in the regulation of cancer drug resistance through cSrc and beta-catenin signaling. Mol. Cancer 2010, 9, 145. [Google Scholar] [CrossRef]
  55. Kramer, R.; Bielawski, J.; Kistner-Griffin, E.; Othman, A.; Alecu, I.; Ernst, D.; Kornhauser, D.; Hornemann, T.; Spassieva, S. Neurotoxic 1-deoxysphingolipids and paclitaxel-induced peripheral neuropathy. FASEB J. 2015, 29, 4461–4472. [Google Scholar] [CrossRef]
  56. Brachtendorf, S.; El-Hindi, K.; Grosch, S. Ceramide synthases in cancer therapy and chemoresistance. Prog. Lipid Res. 2019, 74, 160–185. [Google Scholar] [CrossRef] [PubMed]
  57. Mesicek, J.; Lee, H.; Feldman, T.; Jiang, X.; Skobeleva, A.; Berdyshev, E.V.; Haimovitz-Friedman, A.; Fuks, Z.; Kolesnick, R. Ceramide synthases 2, 5, and 6 confer distinct roles in radiation-induced apoptosis in HeLa cells. Cell Signal 2010, 22, 1300–1307. [Google Scholar] [CrossRef]
  58. Morad, S.A.; Levin, J.C.; Shanmugavelandy, S.S.; Kester, M.; Fabrias, G.; Bedia, C.; Cabot, M.C. Ceramide--antiestrogen nanoliposomal combinations--novel impact of hormonal therapy in hormone-insensitive breast cancer. Mol. Cancer 2012, 11, 2352–2361. [Google Scholar] [CrossRef]
  59. Morad, S.A.; Tan, S.F.; Feith, D.J.; Kester, M.; Claxton, D.F.; Loughran, T.P., Jr.; Barth, B.M.; Fox, T.E.; Cabot, M.C. Modification of sphingolipid metabolism by tamoxifen and N-desmethyltamoxifen in acute myelogenous leukemia--Impact on enzyme activity and response to cytotoxics. Biochim. Biophys. Acta 2015, 1851, 919–928. [Google Scholar] [CrossRef]
  60. El Kaffas, A.; Al-Mahrouki, A.; Hashim, A.; Law, N.; Giles, A.; Czarnota, G.J. Role of Acid Sphingomyelinase and Ceramide in Mechano-Acoustic Enhancement of Tumor Radiation Responses. J. Natl. Cancer Inst. 2018, 110, 1009–1018. [Google Scholar] [CrossRef]
  61. Hait, N.C.; Maiti, A. The Role of Sphingosine-1-Phosphate and Ceramide-1-Phosphate in Inflammation and Cancer. Mediat. Inflamm. 2017, 2017, 4806541. [Google Scholar] [CrossRef]
  62. Zhang, Y.; Zhang, X.; Lu, M.; Zou, X. Ceramide-1-phosphate and its transfer proteins in eukaryotes. Chem. Phys. Lipids 2021, 240, 105135. [Google Scholar] [CrossRef] [PubMed]
  63. Presa, N.; Gomez-Larrauri, A.; Dominguez-Herrera, A.; Trueba, M.; Gomez-Munoz, A. Novel signaling aspects of ceramide 1-phosphate. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 2020, 1865, 158630. [Google Scholar] [CrossRef]
  64. Ruckhaberle, E.; Karn, T.; Rody, A.; Hanker, L.; Gatje, R.; Metzler, D.; Holtrich, U.; Kaufmann, M. Gene expression of ceramide kinase, galactosyl ceramide synthase and ganglioside GD3 synthase is associated with prognosis in breast cancer. J. Cancer Res. Clin Oncol 2009, 135, 1005–1013. [Google Scholar] [CrossRef] [PubMed]
  65. Gomez-Munoz, A. The Role of Ceramide 1-Phosphate in Tumor Cell Survival and Dissemination. Adv. Cancer Res. 2018, 140, 217–234. [Google Scholar] [CrossRef]
  66. Zhu, S.; Xu, Y.; Wang, L.; Liao, S.; Wang, Y.; Shi, M.; Tu, Y.; Zhou, Y.; Wei, W. Ceramide kinase mediates intrinsic resistance and inferior response to chemotherapy in triple-negative breast cancer by upregulating Ras/ERK and PI3K/Akt pathways. Cancer Cell Int. 2021, 21, 42. [Google Scholar] [CrossRef] [PubMed]
  67. Budczies, J.; Pfitzner, B.M.; Gyorffy, B.; Winzer, K.J.; Radke, C.; Dietel, M.; Fiehn, O.; Denkert, C. Glutamate enrichment as new diagnostic opportunity in breast cancer. Int. J. Cancer 2015, 136, 1619–1628. [Google Scholar] [CrossRef]
  68. Simpson, N.E.; Tryndyak, V.P.; Beland, F.A.; Pogribny, I.P. An in vitro investigation of metabolically sensitive biomarkers in breast cancer progression. Breast Cancer Res. Treat. 2012, 133, 959–968. [Google Scholar] [CrossRef]
  69. Schomel, N.; Hancock, S.E.; Gruber, L.; Olzomer, E.M.; Byrne, F.L.; Shah, D.; Hoehn, K.L.; Turner, N.; Grosch, S.; Geisslinger, G.; et al. UGCG influences glutamine metabolism of breast cancer cells. Sci. Rep. 2019, 9, 15665. [Google Scholar] [CrossRef]
  70. Cardoso, M.R.; Santos, J.C.; Ribeiro, M.L.; Talarico, M.C.R.; Viana, L.R.; Derchain, S.F.M. A Metabolomic Approach to Predict Breast Cancer Behavior and Chemotherapy Response. Int. J. Mol. Sci. 2018, 19, 617. [Google Scholar] [CrossRef]
  71. Shajahan-Haq, A.N.; Cheema, M.S.; Clarke, R. Application of metabolomics in drug resistant breast cancer research. Metabolites 2015, 5, 100–118. [Google Scholar] [CrossRef]
  72. Schomel, N.; Gruber, L.; Alexopoulos, S.J.; Trautmann, S.; Olzomer, E.M.; Byrne, F.L.; Hoehn, K.L.; Gurke, R.; Thomas, D.; Ferreiros, N.; et al. UGCG overexpression leads to increased glycolysis and increased oxidative phosphorylation of breast cancer cells. Sci. Rep. 2020, 10, 8182. [Google Scholar] [CrossRef] [PubMed]
  73. Izgordu, H.; Vejselova Sezer, C.; Comlekci, E.; Kutlu, H.M. Characteristics of apoptosis induction in human breast cancer cells treated with a ceramidase inhibitor. Cytotechnology 2020, 72, 907–919, Erratum in Cytotechnology 2021, 73, 139–140. [Google Scholar] [CrossRef] [PubMed]
  74. Ruckhaberle, E.; Holtrich, U.; Engels, K.; Hanker, L.; Gatje, R.; Metzler, D.; Karn, T.; Kaufmann, M.; Rody, A. Acid ceramidase 1 expression correlates with a better prognosis in ER-positive breast cancer. Climacteric 2009, 12, 502–513. [Google Scholar] [CrossRef]
  75. Alshaker, H.; Thrower, H.; Pchejetski, D. Sphingosine Kinase 1 in Breast Cancer-A New Molecular Marker and a Therapy Target. Front. Oncol. 2020, 10, 289. [Google Scholar] [CrossRef]
  76. Fang, T.; Jiang, Y.X.; Chen, L.; Huang, L.; Tian, X.H.; Zhou, Y.D.; Nagle, D.G.; Zhang, D.D. Coix Seed Oil Exerts an Anti-Triple-Negative Breast Cancer Effect by Disrupting miR-205/S1PR1 Axis. Front. Pharm. 2020, 11, 529962. [Google Scholar] [CrossRef] [PubMed]
  77. Alshaker, H.; Srivats, S.; Monteil, D.; Wang, Q.; Low, C.M.R.; Pchejetski, D. Field template-based design and biological evaluation of new sphingosine kinase 1 inhibitors. Breast Cancer Res. Treat. 2018, 172, 33–43. [Google Scholar] [CrossRef] [PubMed]
  78. Ochnik, A.M.; Baxter, R.C. Insulin-like growth factor receptor and sphingosine kinase are prognostic and therapeutic targets in breast cancer. BMC Cancer 2017, 17, 820. [Google Scholar] [CrossRef]
  79. Tsuchida, J.; Nagahashi, M.; Takabe, K.; Wakai, T. Clinical Impact of Sphingosine-1-Phosphate in Breast Cancer. Mediat. Inflamm. 2017, 2017, 2076239. [Google Scholar] [CrossRef]
  80. Marzec, K.A.; Baxter, R.C.; Martin, J.L. Targeting Insulin-Like Growth Factor Binding Protein-3 Signaling in Triple-Negative Breast Cancer. Biomed. Res. Int. 2015, 2015, 638526. [Google Scholar] [CrossRef]
  81. Hii, L.W.; Chung, F.F.; Mai, C.W.; Yee, Z.Y.; Chan, H.H.; Raja, V.J.; Dephoure, N.E.; Pyne, N.J.; Pyne, S.; Leong, C.O. Sphingosine Kinase 1 Regulates the Survival of Breast Cancer Stem Cells and Non-stem Breast Cancer Cells by Suppression of STAT1. Cells 2020, 9, 886. [Google Scholar] [CrossRef]
  82. Alshaker, H.; Wang, Q.; Srivats, S.; Chao, Y.; Cooper, C.; Pchejetski, D. New FTY720-docetaxel nanoparticle therapy overcomes FTY720-induced lymphopenia and inhibits metastatic breast tumour growth. Breast Cancer Res. Treat. 2017, 165, 531–543. [Google Scholar] [CrossRef] [PubMed]
  83. Zheng, K.; Chen, Z.; Feng, H.; Chen, Y.; Zhang, C.; Yu, J.; Luo, Y.; Zhao, L.; Jiang, X.; Shi, F. Sphingomyelin synthase 2 promotes an aggressive breast cancer phenotype by disrupting the homoeostasis of ceramide and sphingomyelin. Cell Death Dis. 2019, 10, 157. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Shammout, O.D.A.; Ashmawy, N.S.; Shakartalla, S.B.; Altaie, A.M.; Semreen, M.H.; Omar, H.A.; Soliman, S.S.M. Comparative sphingolipidomic analysis reveals significant differences between doxorubicin-sensitive and -resistance MCF-7 cells. PLoS ONE 2021, 16, e0258363. [Google Scholar] [CrossRef]
  85. Alshaker, H.; Wang, Q.; Brewer, D.; Pchejetski, D. Transcriptome-Wide Effects of Sphingosine Kinases Knockdown in Metastatic Prostate and Breast Cancer Cells: Implications for Therapeutic Targeting. Front. Pharm. 2019, 10, 303. [Google Scholar] [CrossRef]
  86. Geffken, K.; Spiegel, S. Sphingosine kinase 1 in breast cancer. Adv. Biol. Regul. 2018, 67, 59–65. [Google Scholar] [CrossRef] [PubMed]
  87. Chen, Z.; Liu, B. Sphk1 participates in malignant progression of breast cancer by regulating epithelial-mesenchymal transition and stem cell characteristics. Tissue Cell 2020, 65, 101380. [Google Scholar] [CrossRef] [PubMed]
  88. Sakharkar, M.K.; Kaur Dhillon, S.; Chidambaram, S.B.; Essa, M.M.; Yang, J. Gene Pair Correlation Coefficients in Sphingolipid Metabolic Pathway as a Potential Prognostic Biomarker for Breast Cancer. Cancers 2020, 12, 1747. [Google Scholar] [CrossRef]
  89. Newcomb, B.; Rhein, C.; Mileva, I.; Ahmad, R.; Clarke, C.J.; Snider, J.; Obeid, L.M.; Hannun, Y.A. Identification of an acid sphingomyelinase ceramide kinase pathway in the regulation of the chemokine CCL5. J. Lipid. Res. 2018, 59, 1219–1229. [Google Scholar] [CrossRef]
  90. Schwalm, S.; Erhardt, M.; Romer, I.; Pfeilschifter, J.; Zangemeister-Wittke, U.; Huwiler, A. Ceramide Kinase Is Upregulated in Metastatic Breast Cancer Cells and Contributes to Migration and Invasion by Activation of PI 3-Kinase and Akt. Int. J. Mol. Sci. 2020, 21, 1396. [Google Scholar] [CrossRef]
  91. Pal, P.; Millner, A.; Semina, S.E.; Huggins, R.J.; Running, L.; Aga, D.S.; Tonetti, D.A.; Schiff, R.; Greene, G.L.; Atilla-Gokcumen, G.E.; et al. Endocrine Therapy-Resistant Breast Cancer Cells Are More Sensitive to Ceramide Kinase Inhibition and Elevated Ceramide Levels Than Therapy-Sensitive Breast Cancer Cells. Cancers 2022, 14, 2380. [Google Scholar] [CrossRef]
  92. Granado, M.H.; Gangoiti, P.; Ouro, A.; Arana, L.; Gomez-Munoz, A. Ceramide 1-phosphate inhibits serine palmitoyltransferase and blocks apoptosis in alveolar macrophages. Biochim. Biophys. Acta 2009, 1791, 263–272. [Google Scholar] [CrossRef] [PubMed]
  93. Inwald, E.C.; Klinkhammer-Schalke, M.; Hofstadter, F.; Zeman, F.; Koller, M.; Gerstenhauer, M.; Ortmann, O. Ki-67 is a prognostic parameter in breast cancer patients: Results of a large population-based cohort of a cancer registry. Breast Cancer Res. Treat 2013, 139, 539–552. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Kartal Yandim, M.; Apohan, E.; Baran, Y. Therapeutic potential of targeting ceramide/glucosylceramide pathway in cancer. Cancer Chemother. Pharm. 2013, 71, 13–20. [Google Scholar] [CrossRef] [PubMed]
  95. Li, Z.; Zhang, L.; Liu, D.; Wang, C. Ceramide glycosylation and related enzymes in cancer signaling and therapy. Biomed. Pharm. 2021, 139, 111565. [Google Scholar] [CrossRef]
  96. Zhang, X.; Li, J.; Qiu, Z.; Gao, P.; Wu, X.; Zhou, G. Co-suppression of MDR1 (multidrug resistance 1) and GCS (glucosylceramide synthase) restores sensitivity to multidrug resistance breast cancer cells by RNA interference (RNAi). Cancer Biol. 2009, 8, 1117–1121. [Google Scholar] [CrossRef] [PubMed]
  97. Wegner, M.S.; Schomel, N.; Gruber, L.; Ortel, S.B.; Kjellberg, M.A.; Mattjus, P.; Kurz, J.; Trautmann, S.; Peng, B.; Wegner, M.; et al. UDP-glucose ceramide glucosyltransferase activates AKT, promoted proliferation, and doxorubicin resistance in breast cancer cells. Cell Mol. Life Sci. 2018, 75, 3393–3410. [Google Scholar] [CrossRef]
  98. Jacobs, A.T.; Martinez Castaneda-Cruz, D.; Rose, M.M.; Connelly, L. Targeted therapy for breast cancer: An overview of drug classes and outcomes. Biochem. Pharm. 2022, 204, 115209. [Google Scholar] [CrossRef]
  99. Fisher, B.; Bauer, M.; Margolese, R.; Poisson, R.; Pilch, Y.; Redmond, C.; Fisher, E.; Wolmark, N.; Deutsch, M.; Montague, E.; et al. Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. N. Engl. J. Med. 1985, 312, 665–673. [Google Scholar] [CrossRef]
  100. Clifford, R.E.; Bowden, D.; Blower, E.; Kirwan, C.C.; Vimalachandran, D. Does tamoxifen have a therapeutic role outside of breast cancer? A systematic review of the evidence. Surg. Oncol. 2020, 33, 100–107. [Google Scholar] [CrossRef]
  101. Elojeimy, S.; Holman, D.H.; Liu, X.; El-Zawahry, A.; Villani, M.; Cheng, J.C.; Mahdy, A.; Zeidan, Y.; Bielwaska, A.; Hannun, Y.A.; et al. New insights on the use of desipramine as an inhibitor for acid ceramidase. FEBS Lett. 2006, 580, 4751–4756. [Google Scholar] [CrossRef]
  102. Santana, P.; Pena, L.A.; Haimovitz-Friedman, A.; Martin, S.; Green, D.; McLoughlin, M.; Cordon-Cardo, C.; Schuchman, E.H.; Fuks, Z.; Kolesnick, R. Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis. Cell 1996, 86, 189–199. [Google Scholar] [CrossRef]
  103. Zeidan, Y.H.; Jenkins, R.W.; Hannun, Y.A. Remodeling of cellular cytoskeleton by the acid sphingomyelinase/ceramide pathway. J. Cell Biol. 2008, 181, 335–350. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Heakal, Y.; Kester, M. Nanoliposomal short-chain ceramide inhibits agonist-dependent translocation of neurotensin receptor 1 to structured membrane microdomains in breast cancer cells. Mol. Cancer Res. 2009, 7, 724–734. [Google Scholar] [CrossRef] [PubMed]
  105. Haakenson, J.K.; Khokhlatchev, A.V.; Choi, Y.J.; Linton, S.S.; Zhang, P.; Zaki, P.M.; Fu, C.; Cooper, T.K.; Manni, A.; Zhu, J.; et al. Lysosomal degradation of CD44 mediates ceramide nanoliposome-induced anoikis and diminished extravasation in metastatic carcinoma cells. J. Biol. Chem. 2015, 290, 8632–8643. [Google Scholar] [CrossRef]
  106. Jatoi, A.; Suman, V.J.; Schaefer, P.; Block, M.; Loprinzi, C.; Roche, P.; Garneau, S.; Morton, R.; Stella, P.J.; Alberts, S.R.; et al. A phase II study of topical ceramides for cutaneous breast cancer. Breast Cancer Res. Treat 2003, 80, 99–104. [Google Scholar] [CrossRef]
  107. Lerata, M.S.; D’Souza, S.; Sibuyi, N.R.S.; Dube, A.; Meyer, M.; Samaai, T.; Antunes, E.M.; Beukes, D.R. Encapsulation of Variabilin in Stearic Acid Solid Lipid Nanoparticles Enhances Its Anticancer Activity in Vitro. Molecules 2020, 25, 830. [Google Scholar] [CrossRef]
  108. Lee, S.Y.; Ko, S.H.; Shim, J.S.; Kim, D.D.; Cho, H.J. Tumor Targeting and Lipid Rafts Disrupting Hyaluronic Acid-Cyclodextrin-Based Nanoassembled Structure for Cancer Therapy. ACS Appl. Mater. Interfaces 2018, 10, 36628–36640. [Google Scholar] [CrossRef]
  109. Migotto, A.; Carvalho, V.F.M.; Salata, G.C.; da Silva, F.W.M.; Yan, C.Y.I.; Ishida, K.; Costa-Lotufo, L.V.; Steiner, A.A.; Lopes, L.B. Multifunctional nanoemulsions for intraductal delivery as a new platform for local treatment of breast cancer. Drug Deliv. 2018, 25, 654–667. [Google Scholar] [CrossRef]
  110. Overbye, A.; Holsaeter, A.M.; Markus, F.; Skalko-Basnet, N.; Iversen, T.G.; Torgersen, M.L.; Sonstevold, T.; Engebraaten, O.; Flatmark, K.; Maelandsmo, G.M.; et al. Ceramide-containing liposomes with doxorubicin: Time and cell-dependent effect of C6 and C12 ceramide. Oncotarget 2017, 8, 76921–76934. [Google Scholar] [CrossRef]
  111. Tonelli, F.; Lim, K.G.; Loveridge, C.; Long, J.; Pitson, S.M.; Tigyi, G.; Bittman, R.; Pyne, S.; Pyne, N.J. FTY720 and (S)-FTY720 vinylphosphonate inhibit sphingosine kinase 1 and promote its proteasomal degradation in human pulmonary artery smooth muscle, breast cancer and androgen-independent prostate cancer cells. Cell Signal 2010, 22, 1536–1542. [Google Scholar] [CrossRef]
  112. Azuma, H.; Horie, S.; Muto, S.; Otsuki, Y.; Matsumoto, K.; Morimoto, J.; Gotoh, R.; Okuyama, A.; Suzuki, S.; Katsuoka, Y.; et al. Selective cancer cell apoptosis induced by FTY720; evidence for a Bcl-dependent pathway and impairment in ERK activity. Anticancer Res 2003, 23, 3183–3193. [Google Scholar] [PubMed]
  113. Hait, N.C.; Avni, D.; Yamada, A.; Nagahashi, M.; Aoyagi, T.; Aoki, H.; Dumur, C.I.; Zelenko, Z.; Gallagher, E.J.; Leroith, D.; et al. The phosphorylated prodrug FTY720 is a histone deacetylase inhibitor that reactivates ERalpha expression and enhances hormonal therapy for breast cancer. Oncogenesis 2015, 4, e156. [Google Scholar] [CrossRef] [PubMed]
  114. Rupp, T.; Pelouin, O.; Genest, L.; Legrand, C.; Froget, G.; Castagne, V. Therapeutic potential of Fingolimod in triple negative breast cancer preclinical models. Transl. Oncol. 2021, 14, 100926. [Google Scholar] [CrossRef] [PubMed]
  115. McGowan, E.M.; Alling, N.; Jackson, E.A.; Yagoub, D.; Haass, N.K.; Allen, J.D.; Martinello-Wilks, R. Evaluation of cell cycle arrest in estrogen responsive MCF-7 breast cancer cells: Pitfalls of the MTS assay. PLoS ONE 2011, 6, e20623. [Google Scholar] [CrossRef]
  116. Mousseau, Y.; Mollard, S.; Faucher-Durand, K.; Richard, L.; Nizou, A.; Cook-Moreau, J.; Baaj, Y.; Qiu, H.; Plainard, X.; Fourcade, L.; et al. Fingolimod potentiates the effects of sunitinib malate in a rat breast cancer model. Breast Cancer Res. Treat 2012, 134, 31–40. [Google Scholar] [CrossRef]
  117. Marvaso, G.; Barone, A.; Amodio, N.; Raimondi, L.; Agosti, V.; Altomare, E.; Scotti, V.; Lombardi, A.; Bianco, R.; Bianco, C.; et al. Sphingosine analog fingolimod (FTY720) increases radiation sensitivity of human breast cancer cells in vitro. Cancer Biol. 2014, 15, 797–805. [Google Scholar] [CrossRef] [PubMed]
  118. Katsuta, E.; Yan, L.; Nagahashi, M.; Raza, A.; Sturgill, J.L.; Lyon, D.E.; Rashid, O.M.; Hait, N.C.; Takabe, K. Doxorubicin effect is enhanced by sphingosine-1-phosphate signaling antagonist in breast cancer. J. Surg. Res. 2017, 219, 202–213. [Google Scholar] [CrossRef]
  119. Nagahashi, M.; Yamada, A.; Katsuta, E.; Aoyagi, T.; Huang, W.C.; Terracina, K.P.; Hait, N.C.; Allegood, J.C.; Tsuchida, J.; Yuza, K.; et al. Targeting the SphK1/S1P/S1PR1 Axis That Links Obesity, Chronic Inflammation, and Breast Cancer Metastasis. Cancer Res. 2018, 78, 1713–1725. [Google Scholar] [CrossRef] [PubMed]
  120. Wang, Y.; Ding, Y.; Wang, C.; Gao, M.; Xu, Y.; Ma, X.; Ma, X.; Cui, H.; Li, L. Fenretinide-polyethylene glycol (PEG) conjugate with improved solubility enhanced cytotoxicity to cancer cell and potent in vivo efficacy. Pharm. Dev. Technol. 2020, 25, 962–970. [Google Scholar] [CrossRef]
  121. Decensi, A.; Bonanni, B.; Baglietto, L.; Guerrieri-Gonzaga, A.; Ramazzotto, F.; Johansson, H.; Robertson, C.; Marinucci, I.; Mariette, F.; Sandri, M.T.; et al. A two-by-two factorial trial comparing oral with transdermal estrogen therapy and fenretinide with placebo on breast cancer biomarkers. Clin. Cancer Res. 2004, 10, 4389–4397. [Google Scholar] [CrossRef]
  122. Formelli, F.; Camerini, T.; Cavadini, E.; Appierto, V.; Villani, M.G.; Costa, A.; De Palo, G.; Di Mauro, M.G.; Veronesi, U. Fenretinide breast cancer prevention trial: Drug and retinol plasma levels in relation to age and disease outcome. Cancer Epidemiol Biomark. Prev 2003, 12, 34–41. [Google Scholar]
  123. Veronesi, U.; Mariani, L.; Decensi, A.; Formelli, F.; Camerini, T.; Miceli, R.; Di Mauro, M.G.; Costa, A.; Marubini, E.; Sporn, M.B.; et al. Fifteen-year results of a randomized phase III trial of fenretinide to prevent second breast cancer. Ann. Oncol. 2006, 17, 1065–1071. [Google Scholar] [CrossRef] [PubMed]
  124. Camerini, T.; Mariani, L.; De Palo, G.; Marubini, E.; Di Mauro, M.G.; Decensi, A.; Costa, A.; Veronesi, U. Safety of the synthetic retinoid fenretinide: Long-term results from a controlled clinical trial for the prevention of contralateral breast cancer. J. Clin. Oncol. 2001, 19, 1664–1670. [Google Scholar] [CrossRef] [PubMed]
  125. Johansson, H.; Gandini, S.; Guerrieri-Gonzaga, A.; Iodice, S.; Ruscica, M.; Bonanni, B.; Gulisano, M.; Magni, P.; Formelli, F.; Decensi, A. Effect of fenretinide and low-dose tamoxifen on insulin sensitivity in premenopausal women at high risk for breast cancer. Cancer Res. 2008, 68, 9512–9518. [Google Scholar] [CrossRef] [PubMed]
  126. Johansson, H.; Bonanni, B.; Gandini, S.; Guerrieri-Gonzaga, A.; Cazzaniga, M.; Serrano, D.; Macis, D.; Puccio, A.; Sandri, M.T.; Gulisano, M.; et al. Circulating hormones and breast cancer risk in premenopausal women: A randomized trial of low-dose tamoxifen and fenretinide. Breast Cancer Res. Treat. 2013, 142, 569–578. [Google Scholar] [CrossRef]
  127. Macis, D.; Gandini, S.; Guerrieri-Gonzaga, A.; Johansson, H.; Magni, P.; Ruscica, M.; Lazzeroni, M.; Serrano, D.; Cazzaniga, M.; Mora, S.; et al. Prognostic effect of circulating adiponectin in a randomized 2 x 2 trial of low-dose tamoxifen and fenretinide in premenopausal women at risk for breast cancer. J. Clin. Oncol. 2012, 30, 151–157. [Google Scholar] [CrossRef]
  128. Serrano, D.; Gandini, S.; Guerrieri-Gonzaga, A.; Feroce, I.; Johansson, H.; Macis, D.; Aristarco, V.; Bonanni, B.; DeCensi, A. Quality of Life in a Randomized Breast Cancer Prevention Trial of Low-Dose Tamoxifen and Fenretinide in Premenopausal Women. Cancer Prev. Res. 2018, 11, 811–818. [Google Scholar] [CrossRef] [PubMed]
  129. Decensi, A.; Robertson, C.; Guerrieri-Gonzaga, A.; Serrano, D.; Cazzaniga, M.; Mora, S.; Gulisano, M.; Johansson, H.; Galimberti, V.; Cassano, E.; et al. Randomized double-blind 2 x 2 trial of low-dose tamoxifen and fenretinide for breast cancer prevention in high-risk premenopausal women. J. Clin. Oncol. 2009, 27, 3749–3756. [Google Scholar] [CrossRef]
  130. Acharya, S.; Yao, J.; Li, P.; Zhang, C.; Lowery, F.J.; Zhang, Q.; Guo, H.; Qu, J.; Yang, F.; Wistuba, I.I.; et al. Sphingosine Kinase 1 Signaling Promotes Metastasis of Triple-Negative Breast Cancer. Cancer Res. 2019, 79, 4211–4226. [Google Scholar] [CrossRef]
  131. Ling, L.U.; Tan, K.B.; Lin, H.; Chiu, G.N. The role of reactive oxygen species and autophagy in safingol-induced cell death. Cell Death Dis. 2011, 2, e129. [Google Scholar] [CrossRef]
  132. French, K.J.; Zhuang, Y.; Maines, L.W.; Gao, P.; Wang, W.; Beljanski, V.; Upson, J.J.; Green, C.L.; Keller, S.N.; Smith, C.D. Pharmacology and antitumor activity of ABC294640, a selective inhibitor of sphingosine kinase-2. J. Pharm. Exp. 2010, 333, 129–139. [Google Scholar] [CrossRef] [PubMed]
  133. Antoon, J.W.; White, M.D.; Meacham, W.D.; Slaughter, E.M.; Muir, S.E.; Elliott, S.; Rhodes, L.V.; Ashe, H.B.; Wiese, T.E.; Smith, C.D.; et al. Antiestrogenic effects of the novel sphingosine kinase-2 inhibitor ABC294640. Endocrinology 2010, 151, 5124–5135. [Google Scholar] [CrossRef] [PubMed]
  134. Shi, W.; Ma, D.; Cao, Y.; Hu, L.; Liu, S.; Yan, D.; Zhang, S.; Zhang, G.; Wang, Z.; Wu, J.; et al. SphK2/S1P Promotes Metastasis of Triple-Negative Breast Cancer Through the PAK1/LIMK1/Cofilin1 Signaling Pathway. Front. Mol. Biosci. 2021, 8, 598218. [Google Scholar] [CrossRef] [PubMed]
  135. Antoon, J.W.; Meacham, W.D.; Bratton, M.R.; Slaughter, E.M.; Rhodes, L.V.; Ashe, H.B.; Wiese, T.E.; Burow, M.E.; Beckman, B.S. Pharmacological inhibition of sphingosine kinase isoforms alters estrogen receptor signaling in human breast cancer. J. Mol. Endocrinol. 2011, 46, 205–216. [Google Scholar] [CrossRef]
  136. Gebremeskel, S.; Nelson, A.; Walker, B.; Oliphant, T.; Lobert, L.; Mahoney, D.; Johnston, B. Natural killer T cell immunotherapy combined with oncolytic vesicular stomatitis virus or reovirus treatments differentially increases survival in mouse models of ovarian and breast cancer metastasis. J. Immunother. Cancer Cancer 2021, 9, e002096. [Google Scholar] [CrossRef]
  137. Liu, Y.; Wang, Z.; Yu, F.; Li, M.; Zhu, H.; Wang, K.; Meng, M.; Zhao, W. The Adjuvant of alpha-Galactosylceramide Presented by Gold Nanoparticles Enhances Antitumor Immune Responses of MUC1 Antigen-Based Tumor Vaccines. Int. J. Nanomed. 2021, 16, 403–420. [Google Scholar] [CrossRef] [PubMed]
  138. Companioni, O.; Mir, C.; Garcia-Mayea, Y.; ME, L.L. Targeting Sphingolipids for Cancer Therapy. Front. Oncol. 2021, 11, 745092. [Google Scholar] [CrossRef]
Ijms 23 11178 g001 550
Figure 1. Structures of ceramides and other sphingolipids. (A) The most prevalent sphingoid base in mammals is a C18-sphingosine. General structures of ceramides (B), sphingomyelins (C) and glucosylceramides (D) on the C18-sphingoid backbone (black). Head groups of sphingomyelin and glucosylceramides are shown in blue. The acyl chain (red) length varies from 16 to 26 carbon-containing structures, predominantly in mammalian cells. C16 species are shown here as representative structures.
Figure 1. Structures of ceramides and other sphingolipids. (A) The most prevalent sphingoid base in mammals is a C18-sphingosine. General structures of ceramides (B), sphingomyelins (C) and glucosylceramides (D) on the C18-sphingoid backbone (black). Head groups of sphingomyelin and glucosylceramides are shown in blue. The acyl chain (red) length varies from 16 to 26 carbon-containing structures, predominantly in mammalian cells. C16 species are shown here as representative structures.
Ijms 23 11178 g001
Ijms 23 11178 g002 550
Figure 2. Ceramide production and turnover pathways. Enzymes are depicted in gray. Pro-apoptotic sphingolipids are depicted in red, and pro-proliferative sphingolipids are depicted in green. Diagram was created with Biorender.com.
Figure 2. Ceramide production and turnover pathways. Enzymes are depicted in gray. Pro-apoptotic sphingolipids are depicted in red, and pro-proliferative sphingolipids are depicted in green. Diagram was created with Biorender.com.
Ijms 23 11178 g002
Table
Table 1. List of enzymes and their inhibitors of the ceramide synthesis and turnover pathways.
Table 1. List of enzymes and their inhibitors of the ceramide synthesis and turnover pathways.
Enzyme Name (Abbreviation)Gene Name(s)ActionsMajor Implication(s) in BCInhibitorCitations
Serine palmitoyl transferase (SPT)SPTLC1–3, SPTSSA-BDe novo ceramide synthesisEnzyme activity increases in response to chemo- and radiotherapy [55]
Ceramide synthase CERS1C18:0, C20:0 ceramide synthesisCeramide production under different stimulusFB1 [56]
CERS2C20:0, C22:0, C24:0, C26:0
ceramide synthesis		Long-chain ceramide production; alternative splicing drives aggressive luminal B phenotype[43]
CERS3C16:0, C18:0, C22:0, C24:0 ceramide synthesisCeramide production under different stimulus[44,45,46,47,48,49,56,57]
CERS4C18:0, C20:0, C22:0, C24:0, C26:0 ceramide synthesis
CERS5C14:0, C16:0 C18:0, C18:1 ceramide synthesis
CERS6C14:0, C16:0, C18:0 ceramide synthesisShort-chain ceramide production; inhibits cell proliferation through mTOR pathway.[42]
Sphingomyelinase
(SMase)		SMPD2Ceramide productionInduce cell cycle arrestGW4869[31,32]
SMPD1Ceramide productionActivity is required for chemo and radiotherapy [58,59,60]
Ceramide kinaseCERKC1P generationCell migration and metastasisNVP-231[61,62,63,64,65,66]
UDP-glucose ceramide glucosyltransferaseUGCGGlucosylceramide generationMetabolic reprogramming, increased energy metabolism [67,68,69,70,71,72]
Acid CeramidaseASAH1Sphingosine production and subsequent S1P productionS1P generation for promoting BC growthD-erythro-MAPP[73,74]
Sphingosine kinaseSPHK1/2S1P generationBC growth and proliferationFTY720[75,76,77,78,79,80,81,82]
Sphingomyelin synthaseSGMS1/2SM generationPromoting EMT, metastasis and chemoresistance [83,84]
Table
Table 2. List of ceramide-based therapeutics in preclinical and clinical studies in breast cancer.
Table 2. List of ceramide-based therapeutics in preclinical and clinical studies in breast cancer.
Drug/Compound NameTargetCombinationPhaseCitations
Fingolimod
(FTY720)		Structural analog of sphingosine, S1PR antagonistAlonePreclinical[111,112,113,114,115]
Sunitinib malatePreclinical[116]
RadiationPreclinical[117]
DoxorubicinPreclinical[118]
CisplatinPreclinical[119]
FenretinideInhibit DEGS1/2AlonePreclinical[120]
AlonePhase I/II[121,122,123,124]
TamoxifenPhase I/II[125,126,127,128,129]
SafingolInhibit SPHK1AlonePreclinical[130,131]
ABC294640Inhibit SPHK2 and DEGS1AlonePreclinical[132,133,134]
Ceramide- nanoliposomes (CNL)Ceramide deliveryAlonePreclinical[104,105,106]
TamoxifenPreclinical[58]
SKI-IISPHK1/2 inhibitorAlonePreclinical[78,135]
α-GalCerSynthetic glycolipid α-galactosyl ceramide, a strong immunostimulantAlonePreclinical[136,137]
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Pal, P.; Atilla-Gokcumen, G.E.; Frasor, J. Emerging Roles of Ceramides in Breast Cancer Biology and Therapy. Int. J. Mol. Sci. 2022, 23, 11178. https://doi.org/10.3390/ijms231911178

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Pal P, Atilla-Gokcumen GE, Frasor J. Emerging Roles of Ceramides in Breast Cancer Biology and Therapy. International Journal of Molecular Sciences. 2022; 23(19):11178. https://doi.org/10.3390/ijms231911178

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Pal, Purab, G. Ekin Atilla-Gokcumen, and Jonna Frasor. 2022. "Emerging Roles of Ceramides in Breast Cancer Biology and Therapy" International Journal of Molecular Sciences 23, no. 19: 11178. https://doi.org/10.3390/ijms231911178

APA Style

Pal, P., Atilla-Gokcumen, G. E., & Frasor, J. (2022). Emerging Roles of Ceramides in Breast Cancer Biology and Therapy. International Journal of Molecular Sciences, 23(19), 11178. https://doi.org/10.3390/ijms231911178

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