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17 pages, 2804 KiB

Open AccessArticle

Suppressing VEGF-A/VEGFR-2 Signaling Contributes to the Anti-Angiogenic Effects of PPE8, a Novel Naphthoquinone-Based Compound

by Ming-Jen Hsu, Han-Kun Chen, Jin-Cherng Lien, Yu-Han Huang and Shiu-Wen Huang

Cells 2022, 11(13), 2114; https://doi.org/10.3390/cells11132114 - 5 Jul 2022

Cited by 5 | Viewed by 3010

Abstract

Natural naphthoquinones and their derivatives exhibit a broad spectrum of pharmacological activities and have thus attracted much attention in modern drug discovery. However, it remains unclear whether naphthoquinones are potential drug candidates for anti-angiogenic agents. The aim of this study was to evaluate [...] Read more.

Natural naphthoquinones and their derivatives exhibit a broad spectrum of pharmacological activities and have thus attracted much attention in modern drug discovery. However, it remains unclear whether naphthoquinones are potential drug candidates for anti-angiogenic agents. The aim of this study was to evaluate the anti-angiogenic properties of a novel naphthoquinone derivative, PPE8, and explore its underlying mechanisms. Determined by various assays including BrdU, migration, invasion, and tube formation analyses, PPE8 treatment resulted in the reduction of VEGF-A-induced proliferation, migration, and invasion, as well as tube formation in human umbilical vein endothelial cells (HUVECs). We also used an aorta ring sprouting assay, Matrigel plug assay, and immunoblotting analysis to examine PPE8’s ex vivo and in vivo anti-angiogenic activities and its actions on VEGF-A signaling. It has been revealed that PPE8 inhibited VEGF-A-induced micro vessel sprouting and was capable of suppressing angiogenesis in in vivo models. In addition, PPE8 inhibited VEGF receptor (VEGFR)-2, Src, FAK, ERK1/2, or AKT phosphorylation in HUVECs exposed to VEGF-A, and it also showed significant decline in xenograft tumor growth in vivo. Taken together, these observations indicated that PPE8 may target VEGF-A–VEGFR-2 signaling to reduce angiogenesis. It also supports the role of PPE8 as a potential drug candidate for the development of therapeutic agents in the treatment of angiogenesis-related diseases including cancer. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Cell Signaling and Regulated Cell Death)

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18 pages, 2966 KiB

Open AccessArticle

Prevention of Cell Death by Activation of Hydroxycarboxylic Acid Receptor 1 (GPR81) in Retinal Explants

by Rupali Vohra, Berta Sanz-Morello, Anna Luna Mølgaard Tams, Zaynab Ahmad Mouhammad, Kristine Karla Freude, Jens Hannibal, Blanca Irene Aldana, Linda Hildegaard Bergersen and Miriam Kolko

Cells 2022, 11(13), 2098; https://doi.org/10.3390/cells11132098 - 2 Jul 2022

Cited by 6 | Viewed by 2970

Abstract

Background: Progressive retinal ganglion cell (RGC) dysfunction and death are common characteristics of retinal neurodegenerative diseases. Recently, hydroxycarboxylic acid receptor 1 (HCA₁R, GPR81) was identified as a key modulator of mitochondrial function and cell survival. Thus, we aimed to test whether [...] Read more.

Background: Progressive retinal ganglion cell (RGC) dysfunction and death are common characteristics of retinal neurodegenerative diseases. Recently, hydroxycarboxylic acid receptor 1 (HCA₁R, GPR81) was identified as a key modulator of mitochondrial function and cell survival. Thus, we aimed to test whether activation of HCA₁R with 3,5-Dihydroxybenzoic acid (DHBA) also promotes RGC survival and improves energy metabolism in mouse retinas. Methods: Retinal explants were treated with 5 mM of the HCA₁R agonist, 3,5-DHBA, for 2, 4, 24, and 72 h. Additionally, explants were also treated with 15 mM of L-glutamate to induce toxicity. Tissue survival was assessed through lactate dehydrogenase (LDH) viability assays. RGC survival was measured through immunohistochemical (IHC) staining. Total ATP levels were quantified through bioluminescence assays. Energy metabolism was investigated through stable isotope labeling and gas chromatography-mass spectrometry (GC-MS). Lactate and nitric oxide levels were measured through colorimetric assays. Results: HCA₁R activation with 3,5-DHBAincreased retinal explant survival. During glutamate-induced death, 3,5-DHBA treatment also increased survival. IHC analysis revealed that 3,5-DHBA treatment promoted RGC survival in retinal wholemounts. 3,5-DHBA treatment also enhanced ATP levels in retinal explants, whereas lactate levels decreased. No effects on glucose metabolism were observed, but small changes in lactate metabolism were found. Nitric oxide levels remained unaltered in response to 3,5-DHBA treatment. Conclusion: The present study reveals that activation of HCA₁R with 3,5-DHBA treatment has a neuroprotective effect specifically on RGCs and on glutamate-induced retinal degeneration. Hence, HCA₁R agonist administration may be a potential new strategy for rescuing RGCs, ultimately preventing visual disability. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Cell Signaling and Regulated Cell Death)

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17 pages, 3748 KiB

Open AccessArticle

Stem Cell Factor SOX9 Interacts with a Cell Death Regulator RIPK1 and Results in Escape of Cancer Stem Cell Death

by Mijung Oh, Chaeyeon Son, Seung Bae Rho, Minjeong Kim, Kyoungsook Park and Sang Yong Song

Cells 2022, 11(3), 363; https://doi.org/10.3390/cells11030363 - 21 Jan 2022

Cited by 4 | Viewed by 3522

Abstract

High-grade ovarian cancer (HGOC) is the most lethal gynecological cancer, with high metastasis and recurrence. Cancer stem cells (CSCs) are responsible for its apoptosis resistance, cancer metastasis, and recurrence. Thus, targeting CSCs would be a promising strategy for overcoming chemotherapy resistance and improving [...] Read more.

High-grade ovarian cancer (HGOC) is the most lethal gynecological cancer, with high metastasis and recurrence. Cancer stem cells (CSCs) are responsible for its apoptosis resistance, cancer metastasis, and recurrence. Thus, targeting CSCs would be a promising strategy for overcoming chemotherapy resistance and improving patient prognosis in HGOC. Among upregulated oncogenic proteins in HGOC, we found that transcription factor SOX9 showed a strong correlation with stemness-regulating ALDH1A1 and was localized predominantly in the cytoplasm of HGOC with lymph node metastasis. In order to address the role of unusual cytoplasmic SOX9 and to explore its underlying mechanism in HGOC malignancy, a Y2H assay was used to identify a necroptotic cell death-associated cytoplasmic protein, receptor-interacting serine/threonine protein kinase 1 (RIPK1), as a novel SOX9-interacting partner and further mapped their respective interacting domains. The C-terminal region containing the transactivation domain of SOX9 interacted with the death domain of R1PK1. Consistent with its stemness-promoting function, SOX9 knockdown in vitro resulted in changes in cell morphology, cell cycle, stem cell marker expression, cell invasion, and sphere formation. Furthermore, in vivo knockdown completely inhibited tumor growth in mouse xenograft model. We propose that cytoplasmic SOX9-mediated cell death suppression would contribute to cancer stem cell survival in HGOC. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Cell Signaling and Regulated Cell Death)

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13 pages, 18911 KiB

Open AccessArticle

Selective Interactions of Mouse Melanocortin Receptor Accessory Proteins with Somatostatin Receptors

by Meng Wang, Jing Xu, Xiao-Wei Lei, Cong Zhang, Shang-Yun Liu, Li-Na Jin and Chao Zhang

Cells 2022, 11(2), 267; https://doi.org/10.3390/cells11020267 - 13 Jan 2022

Cited by 4 | Viewed by 2288

Abstract

Somatostatin receptors (SSTRs) are G protein-coupled receptors (GPCRs) known to regulate exocrine secretion, neurotransmission, and inhibit endogenous cell proliferation. SSTR subtypes (SSTR1-SSTR5) exhibit homo- or heterodimerization with unique signaling characteristics. Melanocortin receptor accessory protein 1 (MRAP1) functions as an allosteric modulator of melanocortin [...] Read more.

Somatostatin receptors (SSTRs) are G protein-coupled receptors (GPCRs) known to regulate exocrine secretion, neurotransmission, and inhibit endogenous cell proliferation. SSTR subtypes (SSTR1-SSTR5) exhibit homo- or heterodimerization with unique signaling characteristics. Melanocortin receptor accessory protein 1 (MRAP1) functions as an allosteric modulator of melanocortin receptors and some other GPCRs. In this study, we investigated the differential interaction of MRAP1 and SSTRs and examined the pharmacological modulation of MRAP1 on mouse SSTR2/SSTR3 and SSTR2/SSTR5 heterodimerization in vitro. Our results show that the mouse SSTR2 forms heterodimers with SSTR3 and SSTR5 and that MRAP1 selectively interacts with SSTR3 and SSTR5 but not SSTR2. The interactive binding sites of SSTR2/SSTR3 or SSTR2/SSTR5 with MRAP1 locate on SSTR3 and SSTR5 but not SSTR2. The binding sites of MRAP1 to SSTR3 are extensive, while the ones of SSTR5 are restricted on transmembrane region six and seven. The heterodimerization of mouse SSTR2, SSTR3, and SSTR5 can be modulated by binding protein in addition to an agonist. Upregulation of extracellular signal-regulated kinases phosphorylation, p27^Kip1, and increased cell growth inhibition with the co-expression of SSTR2/SSTR3 or SSTR2/SSTR5 with MRAP1 suggest a regulatory effect of MRAP1 on anti-proliferative response of two SSTR heterodimers. Taken together, these results provide a new insight of MRAP1 on the maintenance and regulation of mouse SSTR dimers which might be helpful to better understand the molecular mechanism involving SSTRs in tumor biology or other human disorders. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Cell Signaling and Regulated Cell Death)

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14 pages, 3062 KiB

Open AccessFeature PaperArticle

The Isoquinoline-Sulfonamide Compound H-1337 Attenuates SU5416/Hypoxia-Induced Pulmonary Arterial Hypertension in Rats

by Hiroki Shoji, Yoko Yoshida, Takayuki Jujo Sanada, Akira Naito, Junko Maruyama, Erquan Zhang, Kengo Sumi, Seiichiro Sakao, Kazuo Maruyama, Hiroyoshi Hidaka and Koichiro Tatsumi

Cells 2022, 11(1), 66; https://doi.org/10.3390/cells11010066 - 27 Dec 2021

Cited by 4 | Viewed by 4556

Abstract

Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure and right heart failure. Selective pulmonary vasodilators have improved the prognosis of PAH; however, they are not able to reverse pulmonary vascular remodeling. Therefore, a search for new treatment agents is required. [...] Read more.

Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure and right heart failure. Selective pulmonary vasodilators have improved the prognosis of PAH; however, they are not able to reverse pulmonary vascular remodeling. Therefore, a search for new treatment agents is required. H-1337 is an isoquinoline-sulfonamide compound that inhibits multiple serine/threonine kinases, including Rho-associated protein kinase (ROCK) and mammalian target of rapamycin (mTOR). Here, we investigated the effects of H-1337 on pulmonary hypertension and remodeling in the pulmonary vasculature and right ventricle in experimental PAH induced by SU5416 and hypoxia exposure. H-1337 and H-1337M1 exerted inhibitory effects on ROCK and Akt. H-1337 inhibited the phosphorylation of myosin light chain and mTOR and suppressed the proliferation of smooth muscle cells in vitro. H-1337 treatment also suppressed the phosphorylation of myosin light chain and mTOR in the pulmonary vasculature and decreased right ventricular systolic pressure and the extent of occlusive pulmonary vascular lesions. Furthermore, H-1337 suppressed aggravation of right ventricle hypertrophy. In conclusion, our data demonstrated that inhibition of ROCK and mTOR pathways with H-1337 suppressed the progression of pulmonary vascular remodeling, pulmonary hypertension, and right ventricular remodeling. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Cell Signaling and Regulated Cell Death)

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14 pages, 26136 KiB

Open AccessArticle

Functional Proteomic Profiling of Triple-Negative Breast Cancer

by Irina Gromova, Jaime A. Espinoza, Morten Grauslund, Eric Santoni-Rugiu, Maj-Lis Møller Talman, Jan van Oostrum and José M. A. Moreira

Cells 2021, 10(10), 2768; https://doi.org/10.3390/cells10102768 - 15 Oct 2021

Cited by 11 | Viewed by 3261

Abstract

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that comprises various disease entities, all of which share a set of common features: a lack of expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, respectively. Because [...] Read more.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that comprises various disease entities, all of which share a set of common features: a lack of expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, respectively. Because of their receptor status, conventional chemotherapy remains the main therapeutic option for TNBC patients. We employed a reverse phase protein array approach (RPPA), complemented by immunohistochemistry, to quantitatively profile the activation state of 84 actionable key signaling intermediates and phosphoproteins in a set of 44 TNBC samples. We performed supervised and unsupervised approaches to proteomic data analysis to identify groups of samples sharing common characteristics that could be amenable to existing therapies. We found the heterogenous activation of multiple pathways, with PI3 K/AKT/mTOR signaling being the most common event. Some specific individualized therapeutic possibilities include the expression of oncogenic KIT in association with cytokeratin 15 and Erk1/2 positive tumors, both of which may have clinical value. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Cell Signaling and Regulated Cell Death)

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23 pages, 4849 KiB

Open AccessArticle

Identification and Characterization of an Affimer Affinity Reagent for the Detection of the cAMP Sensor, EPAC1

by Hanna K. Buist, Urszula Luchowska-Stańska, Boy van Basten, Jessica Valli, Brian O. Smith, George S. Baillie, Colin Rickman, Bryon Ricketts, Alex Davidson, Ryan Hannam, Joanne Sunderland and Stephen J. Yarwood

Cells 2021, 10(9), 2307; https://doi.org/10.3390/cells10092307 - 3 Sep 2021

Cited by 1 | Viewed by 3568

Abstract

An exchange protein directly activated by cAMP 1 (EPAC1) is an intracellular sensor for cAMP that is involved in a wide variety of cellular and physiological processes in health and disease. However, reagents are lacking to study its association with intracellular cAMP nanodomains. [...] Read more.

An exchange protein directly activated by cAMP 1 (EPAC1) is an intracellular sensor for cAMP that is involved in a wide variety of cellular and physiological processes in health and disease. However, reagents are lacking to study its association with intracellular cAMP nanodomains. Here, we use non-antibody Affimer protein scaffolds to develop isoform-selective protein binders of EPAC1. Phage-display screens were carried out against purified, biotinylated human recombinant EPAC1ΔDEP protein (amino acids 149–811), which identified five potential EPAC1-selective Affimer binders. Dot blots and indirect ELISA assays were next used to identify Affimer 780A as the top EPAC1 binder. Mutagenesis studies further revealed a potential interaction site for 780A within the EPAC1 cyclic nucleotide binding domain (CNBD). In addition, 780A was shown to co-precipitate EPAC1 from transfected cells and co-localize with both wild-type EPAC1 and a mis-targeting mutant of EPAC1(K212R), predominantly in perinuclear and cytosolic regions of cells, respectively. As a novel EPAC1-selective binder, 780A therefore has the potential to be used in future studies to further understand compartmentalization of the cAMP-EPAC1 signaling system. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Cell Signaling and Regulated Cell Death)

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22 pages, 10108 KiB

Open AccessArticle

Pan-Cancer Molecular Patterns and Biological Implications Associated with a Tumor-Specific Molecular Signature

by Darío Rocha, Iris A. García, Aldana González Montoro, Andrea Llera, Laura Prato, María R. Girotti, Gastón Soria and Elmer A. Fernández

Cells 2021, 10(1), 45; https://doi.org/10.3390/cells10010045 - 31 Dec 2020

Cited by 6 | Viewed by 4613

Abstract

Studying tissue-independent components of cancer and defining pan-cancer subtypes could be addressed using tissue-specific molecular signatures if classification errors are controlled. Since PAM50 is a well-known, United States Food and Drug Administration (FDA)-approved and commercially available breast cancer signature, we applied it with [...] Read more.

Studying tissue-independent components of cancer and defining pan-cancer subtypes could be addressed using tissue-specific molecular signatures if classification errors are controlled. Since PAM50 is a well-known, United States Food and Drug Administration (FDA)-approved and commercially available breast cancer signature, we applied it with uncertainty assessment to classify tumor samples from over 33 cancer types, discarded unassigned samples, and studied the emerging tumor-agnostic molecular patterns. The percentage of unassigned samples ranged between 55.5% and 86.9% in non-breast tissues, and gene set analysis suggested that the remaining samples could be grouped into two classes (named C1 and C2) regardless of the tissue. The C2 class was more dedifferentiated, more proliferative, with higher centrosome amplification, and potentially more TP53 and RB1 mutations. We identified 28 gene sets and 95 genes mainly associated with cell-cycle progression, cell-cycle checkpoints, and DNA damage that were consistently exacerbated in the C2 class. In some cancer types, the C1/C2 classification was associated with survival and drug sensitivity, and modulated the prognostic meaning of the immune infiltrate. Our results suggest that PAM50 could be repurposed for a pan-cancer context when paired with uncertainty assessment, resulting in two classes with molecular, biological, and clinical implications. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Cell Signaling and Regulated Cell Death)

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Review

Jump to: Research

11 pages, 903 KiB

Open AccessReview

Regulation of Life & Death by REGγ

by Keaton E. Funderburk, Jungseog Kang and Henry J. Li

Cells 2022, 11(15), 2281; https://doi.org/10.3390/cells11152281 - 23 Jul 2022

Cited by 8 | Viewed by 2886

Abstract

REGγ, a proteasome activator belonging to the 11S (otherwise known as REG, PA28, or PSME) proteasome activator family, is widely present in many eukaryotes. By binding to the 20S catalytic core particle, REGγ acts as a molecular sieve to selectively target proteins for [...] Read more.

REGγ, a proteasome activator belonging to the 11S (otherwise known as REG, PA28, or PSME) proteasome activator family, is widely present in many eukaryotes. By binding to the 20S catalytic core particle, REGγ acts as a molecular sieve to selectively target proteins for degradation in an ATP- and ubiquitin-independent manner. This non-canonical proteasome pathway directly regulates seemingly unrelated cellular processes including cell growth and proliferation, apoptosis, DNA damage response, immune response, and metabolism. By affecting different pathways, REGγ plays a vital role in the regulation of cellular life and death through the maintenance of protein homeostasis. As a promoter of cellular growth and a key regulator of several tumor suppressors, many recent studies have linked REGγ overexpression with tumor formation and suggested the REGγ-proteasome as a potential target of new cancer-drug development. This review will present an overview of the major functions of REGγ as it relates to the regulation of cellular life and death, along with new mechanistic insights into the regulation of REGγ. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Cell Signaling and Regulated Cell Death)

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48 pages, 3107 KiB

Open AccessReview

Normal and Neoplastic Growth Suppression by the Extended Myc Network

by Edward V. Prochownik and Huabo Wang

Cells 2022, 11(4), 747; https://doi.org/10.3390/cells11040747 - 21 Feb 2022

Cited by 12 | Viewed by 3935

Abstract

Among the first discovered and most prominent cellular oncogenes is MYC, which encodes a bHLH-ZIP transcription factor (Myc) that both activates and suppresses numerous genes involved in proliferation, energy production, metabolism and translation. Myc belongs to a small group of bHLH-ZIP transcriptional regulators [...] Read more.

Among the first discovered and most prominent cellular oncogenes is MYC, which encodes a bHLH-ZIP transcription factor (Myc) that both activates and suppresses numerous genes involved in proliferation, energy production, metabolism and translation. Myc belongs to a small group of bHLH-ZIP transcriptional regulators (the Myc Network) that includes its obligate heterodimerization partner Max and six “Mxd proteins” (Mxd1–4, Mnt and Mga), each of which heterodimerizes with Max and largely opposes Myc’s functions. More recently, a second group of bHLH-ZIP proteins (the Mlx Network) has emerged that bears many parallels with the Myc Network. It is comprised of the Myc-like factors ChREBP and MondoA, which, in association with the Max-like member Mlx, regulate smaller and more functionally restricted repertoires of target genes, some of which are shared with Myc. Opposing ChREBP and MondoA are heterodimers comprised of Mlx and Mxd1, Mxd4 and Mnt, which also structurally and operationally link the two Networks. We discuss here the functions of these “Extended Myc Network” members, with particular emphasis on their roles in suppressing normal and neoplastic growth. These roles are complex due to the temporal- and tissue-restricted expression of Extended Myc Network proteins in normal cells, their regulation of both common and unique target genes and, in some cases, their functional redundancy. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Cell Signaling and Regulated Cell Death)

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15 pages, 1371 KiB

Open AccessReview

Genetic Control of MAP3K1 in Eye Development and Sex Differentiation

by Jingjing Wang, Eiki Kimura, Maureen Mongan and Ying Xia

Cells 2022, 11(1), 34; https://doi.org/10.3390/cells11010034 - 23 Dec 2021

Cited by 9 | Viewed by 3560

Abstract

The MAP3K1 is responsible for transmitting signals to activate specific MAP2K-MAPK cascades. Following the initial biochemical characterization, genetic mouse models have taken center stage to elucidate how MAP3K1 regulates biological functions. To that end, mice were generated with the ablation of the entire [...] Read more.

The MAP3K1 is responsible for transmitting signals to activate specific MAP2K-MAPK cascades. Following the initial biochemical characterization, genetic mouse models have taken center stage to elucidate how MAP3K1 regulates biological functions. To that end, mice were generated with the ablation of the entire Map3k1 gene, the kinase domain coding sequences, or ubiquitin ligase domain mutations. Analyses of the mutants identify diverse roles that MAP3K1 plays in embryonic survival, maturation of T/B cells, and development of sensory organs, including eye and ear. Specifically in eye development, Map3k1 loss-of-function was found to be autosomal recessive for congenital eye abnormalities, but became autosomal dominant in combination with Jnk and RhoA mutations. Additionally, Map3k1 mutation increased eye defects with an exposure to environmental agents such as dioxin. Data from eye developmental models reveal the nexus role of MAP3K1 in integrating genetic and environmental signals to control developmental activities. Here, we focus the discussions on recent advances in understanding the signaling mechanisms of MAP3K1 in eye development in mice and in sex differentiation from human genomics findings. The research works featured here lead to a deeper understanding of the in vivo signaling network, the mechanisms of gene–environment interactions, and the relevance of this multifaceted protein kinase in disease etiology and pathogenesis. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Cell Signaling and Regulated Cell Death)

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13 pages, 642 KiB

Open AccessReview

The Use of Nanomedicine to Target Signaling by the PAK Kinases for Disease Treatment

by Yiling Wang and Audrey Minden

Cells 2021, 10(12), 3565; https://doi.org/10.3390/cells10123565 - 17 Dec 2021

Cited by 3 | Viewed by 2976

Abstract

P21-activated kinases (PAKs) are serine/threonine kinases involved in the regulation of cell survival, proliferation, inhibition of apoptosis, and the regulation of cell morphology. Some members of the PAK family are highly expressed in several types of cancer, and they have also been implicated [...] Read more.

P21-activated kinases (PAKs) are serine/threonine kinases involved in the regulation of cell survival, proliferation, inhibition of apoptosis, and the regulation of cell morphology. Some members of the PAK family are highly expressed in several types of cancer, and they have also been implicated in several other medical disorders. They are thus considered to be good targets for treatment of cancer and other diseases. Although there are several inhibitors of the PAKs, the utility of some of these inhibitors is reduced for several reasons, including limited metabolic stability. One way to overcome this problem is the use of nanoparticles, which have the potential to increase drug delivery. The overall goals of this review are to describe the roles for PAK kinases in cell signaling and disease, and to describe how the use of nanomedicine is a promising new method for administering PAK inhibitors for the purpose of disease treatment and research. We discuss some of the basic mechanisms behind nanomedicine technology, and we then describe how these techniques are being used to package and deliver PAK inhibitors. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Cell Signaling and Regulated Cell Death)

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12 pages, 4858 KiB

Open AccessReview

Commander Complex—A Multifaceted Operator in Intracellular Signaling and Cargo

by Saara Laulumaa and Markku Varjosalo

Cells 2021, 10(12), 3447; https://doi.org/10.3390/cells10123447 - 7 Dec 2021

Cited by 7 | Viewed by 4516

Abstract

Commander complex is a 16-protein complex that plays multiple roles in various intracellular events in endosomal cargo and in the regulation of cell homeostasis, cell cycle and immune response. It consists of COMMD1–10, CCDC22, CCDC93, DENND10, VPS26C, VPS29, and VPS35L. These proteins are [...] Read more.

Commander complex is a 16-protein complex that plays multiple roles in various intracellular events in endosomal cargo and in the regulation of cell homeostasis, cell cycle and immune response. It consists of COMMD1–10, CCDC22, CCDC93, DENND10, VPS26C, VPS29, and VPS35L. These proteins are expressed ubiquitously in the human body, and they have been linked to diseases including Wilson’s disease, atherosclerosis, and several types of cancer. In this review we describe the function of the commander complex in endosomal cargo and summarize the individual known roles of COMMD proteins in cell signaling and cancer. It becomes evident that commander complex might be a much more important player in intracellular regulation than we currently understand, and more systematic research on the role of commander complex is required. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Cell Signaling and Regulated Cell Death)

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14 pages, 686 KiB

Open AccessFeature PaperReview

Calcium Signaling Mediates Cell Death and Crosstalk with Autophagy in Kidney Disease

by Bo Ning, Chuanzhi Guo, Anqi Kong, Kongdong Li, Yimin Xie, Haifeng Shi and Jie Gu

Cells 2021, 10(11), 3204; https://doi.org/10.3390/cells10113204 - 17 Nov 2021

Cited by 21 | Viewed by 4460

Abstract

The kidney is an important organ for the maintenance of Ca²⁺ homeostasis in the body. However, disruption of Ca²⁺ homeostasis will cause a series of kidney diseases, such as acute kidney injury (AKI), chronic kidney disease (CKD), renal ischemia/reperfusion (I/R) injury, [...] Read more.

The kidney is an important organ for the maintenance of Ca²⁺ homeostasis in the body. However, disruption of Ca²⁺ homeostasis will cause a series of kidney diseases, such as acute kidney injury (AKI), chronic kidney disease (CKD), renal ischemia/reperfusion (I/R) injury, autosomal dominant polycystic kidney disease (ADPKD), podocytopathy, and diabetic nephropathy. During the progression of kidney disease, Ca²⁺ signaling plays key roles in various cell activities such as necrosis, apoptosis, eryptosis and autophagy. Importantly, there are complex Ca²⁺ flux networks between the endoplasmic reticulum (ER), mitochondria and lysosomes which regulate intracellular Ca²⁺ signaling in renal cells and contribute to kidney disease. In addition, Ca²⁺ signaling also links the crosstalk between various cell deaths and autophagy under the stress of heavy metals or high glucose. In this regard, we present a review of Ca²⁺ signaling in cell death and crosstalk with autophagy and its potential as a therapeutic target for the development of new and efficient drugs against kidney diseases. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Cell Signaling and Regulated Cell Death)

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25 pages, 3916 KiB

Open AccessFeature PaperReview

Positive Regulation of Estrogen Receptor Alpha in Breast Tumorigenesis

by Lucas Porras, Houssam Ismail and Sylvie Mader

Cells 2021, 10(11), 2966; https://doi.org/10.3390/cells10112966 - 31 Oct 2021

Cited by 29 | Viewed by 6972

Abstract

Estrogen receptor alpha (ERα, NR3A1) contributes through its expression in different tissues to a spectrum of physiological processes, including reproductive system development and physiology, bone mass maintenance, as well as cardiovascular and central nervous system functions. It is also one of the main [...] Read more.

Estrogen receptor alpha (ERα, NR3A1) contributes through its expression in different tissues to a spectrum of physiological processes, including reproductive system development and physiology, bone mass maintenance, as well as cardiovascular and central nervous system functions. It is also one of the main drivers of tumorigenesis in breast and uterine cancer and can be targeted by several types of hormonal therapies. ERα is expressed in a subset of luminal cells corresponding to less than 10% of normal mammary epithelial cells and in over 70% of breast tumors (ER+ tumors), but the basis for its selective expression in normal or cancer tissues remains incompletely understood. The mapping of alternative promoters and regulatory elements has delineated the complex genomic structure of the ESR1 gene and shed light on the mechanistic basis for the tissue-specific regulation of ESR1 expression. However, much remains to be uncovered to better understand how ESR1 expression is regulated in breast cancer. This review recapitulates the current body of knowledge on the structure of the ESR1 gene and the complex mechanisms controlling its expression in breast tumors. In particular, we discuss the impact of genetic alterations, chromatin modifications, and enhanced expression of other luminal transcription regulators on ESR1 expression in tumor cells. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Cell Signaling and Regulated Cell Death)

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20 pages, 1989 KiB

Open AccessReview

Targeting Canonical and Non-Canonical STAT Signaling Pathways in Renal Diseases

by Lili Gai, Yuting Zhu, Chun Zhang and Xianfang Meng

Cells 2021, 10(7), 1610; https://doi.org/10.3390/cells10071610 - 27 Jun 2021

Cited by 11 | Viewed by 3839

Abstract

Signal transducer and activator of transcription (STAT) plays an essential role in the inflammatory reaction and immune response of numerous renal diseases. STATs can transmit the signals of cytokines, chemokines, and growth factors from the cell membrane to the nucleus. In the canonical [...] Read more.

Signal transducer and activator of transcription (STAT) plays an essential role in the inflammatory reaction and immune response of numerous renal diseases. STATs can transmit the signals of cytokines, chemokines, and growth factors from the cell membrane to the nucleus. In the canonical STAT signaling pathways, upon binding with their cognate receptors, cytokines lead to a caspase of Janus kinases (JAKs) and STATs tyrosine phosphorylation and activation. Besides receptor-associated tyrosine kinases JAKs, receptors with intrinsic tyrosine kinase activities, G-protein coupled receptors, and non-receptor tyrosine kinases can also activate STATs through tyrosine phosphorylation or, alternatively, other post-translational modifications. Activated STATs translocate into the nucleus and mediate the transcription of specific genes, thus mediating the progression of various renal diseases. Non-canonical STAT pathways consist of preassembled receptor complexes, preformed STAT dimers, unphosphorylated STATs (U-STATs), and non-canonical functions including mitochondria modulation, microtubule regulation and heterochromatin stabilization. Most studies targeting STAT signaling pathways have focused on canonical pathways, but research extending into non-canonical STAT pathways would provide novel strategies for treating renal diseases. In this review, we will introduce both canonical and non-canonical STAT pathways and their roles in a variety of renal diseases. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Cell Signaling and Regulated Cell Death)

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33 pages, 425 KiB

Open AccessFeature PaperReview

The Role of Prostaglandins in Different Types of Cancer

by Álvaro Jara-Gutiérrez and Victoriano Baladrón

Cells 2021, 10(6), 1487; https://doi.org/10.3390/cells10061487 - 13 Jun 2021

Cited by 65 | Viewed by 6413

Abstract

The prostaglandins constitute a family of lipids of 20 carbon atoms that derive from polyunsaturated fatty acids such as arachidonic acid. Traditionally, prostaglandins have been linked to inflammation, female reproductive cycle, vasodilation, or bronchodilator/bronchoconstriction. Recent studies have highlighted the involvement of these lipids [...] Read more.

The prostaglandins constitute a family of lipids of 20 carbon atoms that derive from polyunsaturated fatty acids such as arachidonic acid. Traditionally, prostaglandins have been linked to inflammation, female reproductive cycle, vasodilation, or bronchodilator/bronchoconstriction. Recent studies have highlighted the involvement of these lipids in cancer. In this review, existing information on the prostaglandins associated with different types of cancer and the advances related to the potential use of them in neoplasm therapies have been analyzed. We can conclude that the effect of prostaglandins depends on multiple factors, such as the target tissue, their plasma concentration, and the prostaglandin subtype, among others. Prostaglandin D2 (PGD₂) seems to hinder tumor progression, while prostaglandin E2 (PGE₂) and prostaglandin F2 alpha (PGF_2α) seem to provide greater tumor progression and aggressiveness. However, more studies are needed to determine the role of prostaglandin I2 (PGI₂) and prostaglandin J2 (PGJ₂) in cancer due to the conflicting data obtained. On the other hand, the use of different NSAIDs (non-steroidal anti-inflammatory drugs), especially those selective of COX-2 (cyclooxygenase 2), could have a crucial role in the fight against different neoplasms, either as prophylaxis or as an adjuvant treatment. In addition, multiple targets, related to the action of prostaglandins on the intracellular signaling pathways that are involved in cancer, have been discovered. Thus, in depth research about the prostaglandins involved in different cancer and the different targets modulated by them, as well as their role in the tumor microenvironment and the immune response, is necessary to obtain better therapeutic tools to fight cancer. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Cell Signaling and Regulated Cell Death)

19 pages, 1987 KiB

Open AccessReview

A Potential Role for HUWE1 in Modulating Cisplatin Sensitivity

by Stijn Wenmaekers, Bastiaan J. Viergever, Gunjan Kumar, Onno Kranenburg, Peter C. Black, Mads Daugaard and Richard P. Meijer

Cells 2021, 10(5), 1262; https://doi.org/10.3390/cells10051262 - 20 May 2021

Cited by 11 | Viewed by 5643

Abstract

Cisplatin is a widely used antineoplastic agent, whose efficacy is limited by primary and acquired therapeutic resistance. Recently, a bladder cancer genome-wide CRISPR/Cas9 knock-out screen correlated cisplatin sensitivity to multiple genetic biomarkers. Among the screen’s top hits was the HECT domain-containing ubiquitin E3 [...] Read more.

Cisplatin is a widely used antineoplastic agent, whose efficacy is limited by primary and acquired therapeutic resistance. Recently, a bladder cancer genome-wide CRISPR/Cas9 knock-out screen correlated cisplatin sensitivity to multiple genetic biomarkers. Among the screen’s top hits was the HECT domain-containing ubiquitin E3 ligase (HUWE1). In this review, HUWE1 is postulated as a therapeutic response modulator, affecting the collision between platinum-DNA adducts and the replication fork, the primary cytotoxic action of platins. HUWE1 can alter the cytotoxic response to platins by targeting essential components of the DNA damage response including BRCA1, p53, and Mcl-1. Deficiency of HUWE1 could lead to enhanced DNA damage repair and a dysfunctional apoptotic apparatus, thereby inducing resistance to platins. Future research on the relationship between HUWE1 and platins could generate new mechanistic insights into therapy resistance. Ultimately, HUWE1 might serve as a clinical biomarker to tailor cancer treatment strategies, thereby improving cancer care and patient outcomes. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Cell Signaling and Regulated Cell Death)

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20 pages, 947 KiB

Open AccessReview

Dysregulation of Multiple Signaling Neurodevelopmental Pathways during Embryogenesis: A Possible Cause of Autism Spectrum Disorder

by Jyoti Upadhyay, Jeevan Patra, Nidhi Tiwari, Nilima Salankar, Mohd Nazam Ansari and Wasim Ahmad

Cells 2021, 10(4), 958; https://doi.org/10.3390/cells10040958 - 20 Apr 2021

Cited by 18 | Viewed by 6267

Abstract

Understanding the autistic brain and the involvement of genetic, non-genetic, and numerous signaling pathways in the etiology and pathophysiology of autism spectrum disorder (ASD) is complex, as is evident from various studies. Apart from multiple developmental disorders of the brain, autistic subjects show [...] Read more.

Understanding the autistic brain and the involvement of genetic, non-genetic, and numerous signaling pathways in the etiology and pathophysiology of autism spectrum disorder (ASD) is complex, as is evident from various studies. Apart from multiple developmental disorders of the brain, autistic subjects show a few characteristics like impairment in social communications related to repetitive, restricted, or stereotypical behavior, which suggests alterations in neuronal circuits caused by defects in various signaling pathways during embryogenesis. Most of the research studies on ASD subjects and genetic models revealed the involvement of mutated genes with alterations of numerous signaling pathways like Wnt, hedgehog, and Retinoic Acid (RA). Despite significant improvement in understanding the pathogenesis and etiology of ASD, there is an increasing awareness related to it as well as a need for more in-depth research because no effective therapy has been developed to address ASD symptoms. Therefore, identifying better therapeutic interventions like “novel drugs for ASD” and biomarkers for early detection and disease condition determination are required. This review article investigated various etiological factors as well as the signaling mechanisms and their alterations to understand ASD pathophysiology. It summarizes the mechanism of signaling pathways, their significance, and implications for ASD. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Cell Signaling and Regulated Cell Death)

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