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Cancer Metabolism—Metabolites Regulation of Oncogenic Signaling and Epigenetics

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 January 2020) | Viewed by 65873

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Dr. Jun-ichi Hanai

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Department of Medicine, Massachusetts General Hospital, Center for Cancer Research, Harvard Medical School, Boston, MA 02215, USA
Interests: oncogenic stem cells; EMT (epithelial mesenchymal transition); fibrosis; vascular pathology; aging
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Dear Colleagues,

This Special Issue focuses on mechanisms and regulations in the altered metabolic pathways in cancer cells.

Cancer has been considered a disorder of proliferation, but recent evidence suggests that cancer is also a metabolic disease. The fact that growing tumors rewire their metabolic programs was first recognized almost a century ago. Now, links between oncogenic pathways and cancer-cell metabolism have been established. Cancer cells alter their metabolism to meet their energetic and anabolic demands and to survive in hostile environments.

The cancer metabolome is extremely flexible, creating challenges for drug discovery, as cancers can often bypass the effects of a small molecule by shifting pathways. A better understanding of cancer-specific metabolic processes may revolutionize cancer treatment.

Metabolic remodeling in cancer creates metabolites that control the signaling and epigenetic pathways that drive tumors. Understanding the interaction between metabolism and signaling/epigenetic pathways could reveal new vulnerabilities of cancer.

We welcome submissions, including original manuscripts and reviews, on this important topic.

Dr. Jun-ichi Hanai
Guest Editor

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Keywords

impact of oncogenic signaling on metabolism
alterations in metabolite-driven gene regulation and signaling pathways
metabolic wiring
metabolic control of the epigenome
metabolic heterogeneity and cancer progression
targeting metabolic liabilities
targeting stroma metabolism
cancer metabolism influenced by systemic metabolic status
immunometabolism
redox metabolism
the influence of metabolism on metastasis and progression
Warburg in non-cancer diseases, inflammation
metabolism-based imaging
preclinical and clinical studies of metabolism-related cancer therapies

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Cancer Metabolism—Metabolites Regulation of Oncogenic Signaling and Epigenetics 2.0 in International Journal of Molecular Sciences (1 article)

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Research

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12 pages, 3656 KiB

Open AccessArticle

Early Detection of Pancreatic Intraepithelial Neoplasias (PanINs) in Transgenic Mouse Model by Hyperpolarized ¹³C Metabolic Magnetic Resonance Spectroscopy

by Prasanta Dutta, Susana Castro Pando, Marilina Mascaro, Erick Riquelme, Michelle Zoltan, Niki M. Zacharias, Seth T. Gammon, David Piwnica-Worms, Mark D. Pagel, Subrata Sen, Anirban Maitra, Shayan Shams, Florencia McAllister and Pratip K. Bhattacharya

Int. J. Mol. Sci. 2020, 21(10), 3722; https://doi.org/10.3390/ijms21103722 - 25 May 2020

Cited by 11 | Viewed by 3998

Abstract

While pancreatic cancer (PC) survival rates have recently shown modest improvement, the disease remains largely incurable. Early detection of pancreatic cancer may result in improved outcomes and therefore, methods for early detection of cancer, even premalignant lesions, may provide more favorable outcomes. Pancreatic intraepithelial neoplasias (PanINs) have been identified as premalignant precursor lesions to pancreatic cancer. However, conventional imaging methods used for screening high-risk populations do not have the sensitivity to detect PanINs. Here, we have employed hyperpolarized metabolic imaging in vivo and nuclear magnetic resonance (¹H-NMR) metabolomics ex vivo to identify and understand metabolic changes, towards enabling detection of early PanINs and progression to advanced PanINs lesions that precede pancreatic cancer formation. Progression of disease from tissue containing predominantly low-grade PanINs to tissue with high-grade PanINs showed a decreasing alanine/lactate ratio from high-resolution NMR metabolomics ex vivo. Hyperpolarized magnetic resonance spectroscopy (HP-MRS) allows over 10,000-fold sensitivity enhancement relative to conventional magnetic resonance. Real-time HP-MRS was employed to measure non-invasively changes of alanine and lactate metabolites with disease progression and in control mice in vivo, following injection of hyperpolarized [1-¹³C] pyruvate. The alanine-to-lactate signal intensity ratio was found to decrease as the disease progressed from low-grade PanINs to high-grade PanINs. The biochemical changes of alanine transaminase (ALT) and lactate dehydrogenase (LDH) enzyme activity were assessed. These results demonstrate that there are significant alterations of ALT and LDH activities during the transformation from early to advanced PanINs lesions. Furthermore, we demonstrate that real-time conversion kinetic rate constants (k_PA and k_PL) can be used as metabolic imaging biomarkers of pancreatic premalignant lesions. Findings from this emerging HP-MRS technique can be translated to the clinic for detection of pancreatic premalignant lesion in high-risk populations. Full article

(This article belongs to the Special Issue Cancer Metabolism—Metabolites Regulation of Oncogenic Signaling and Epigenetics)

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15 pages, 2166 KiB

Open AccessArticle

Co-Expression Effect of SLC7A5/SLC3A2 to Predict Response to Endocrine Therapy in Oestrogen-Receptor-Positive Breast Cancer

by Lutfi H. Alfarsi, Rokaya El-Ansari, Madeleine L. Craze, Brendah K. Masisi, Omar J. Mohammed, Ian O. Ellis, Emad A. Rakha and Andrew R. Green

Int. J. Mol. Sci. 2020, 21(4), 1407; https://doi.org/10.3390/ijms21041407 - 19 Feb 2020

Cited by 26 | Viewed by 4766

Abstract

The majority of breast cancers are oestrogen-receptor-positive (ER+) and are subject to endocrine therapy; however, an unpredictable subgroup of patients will develop resistance to endocrine therapy. The SLC7A5/SLC3A2 complex is a major route for the transport of large neutral essential amino acids through the plasma membrane. Alterations in the expression and function of those amino-acid transporters lead to metabolic reprogramming, which contributes to the tumorigenesis and drug resistance. This study aims to assess the effects and roles of SLC7A5/SLC3A2 co-expression in predicting responses to endocrine therapy in patients with ER+ breast cancer. The biological and clinical impact of SLC7A5/SLC3A2 co-expression was assessed in large annotated cohorts of ER+/HER2− breast cancer with long-term follow-up at the mRNA and protein levels. In vitro experiments were conducted to investigate the effect of SLC7A5/SLC3A2 knockdown in the proliferation of cancer cells and to the sensitivity to tamoxifen. We found that proliferation-related genes are highly expressed in a subgroup of patients with high SLC7A5/SLC3A2, and knockdown of SLC7A5/SLC3A2 decreased proliferation of ER+ breast cancer cells. In patients treated with endocrine therapy, high SLC7A5/SLC3A2 co-expression was associated with poor patient outcome, and depletion of SLC7A5/SLC3A2 using siRNA increased the sensitivity of breast cancer cells to tamoxifen. On the basis of our findings, SLC7A5/SLC3A2 co-expression has the potential of identifying a subgroup of ER+/HER2− breast cancer patients who fail to benefit from endocrine therapy and could guide the choice of other alternative therapies. Full article

(This article belongs to the Special Issue Cancer Metabolism—Metabolites Regulation of Oncogenic Signaling and Epigenetics)

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14 pages, 2793 KiB

Open AccessArticle

EHMT2 Inhibition Induces Cell Death in Human Non-Small Cell Lung Cancer by Altering the Cholesterol Biosynthesis Pathway

by Haeun Kim, Seo Yoon Choi, Jinyeong Lim, Anders M. Lindroth and Yoon Jung Park

Int. J. Mol. Sci. 2020, 21(3), 1002; https://doi.org/10.3390/ijms21031002 - 3 Feb 2020

Cited by 18 | Viewed by 4368

Abstract

Non-small cell lung cancer (NSCLC) is a major subtype of lung cancer. Besides genetic and environmental factors, epigenetic alterations contribute to the tumorigenesis of NSCLC. Epigenetic changes are considered key drivers of cancer initiation and progression, and altered expression and activity of epigenetic modifiers reshape the epigenetic landscape in cancer cells. Euchromatic histone-lysine N-methyltransferase 2 (EHMT2) is a histone methyltransferase and catalyzes mono- and di-methylation at histone H3 lysine 9 (H3K9me1 and H3K9me2, respectively), leading to gene silencing. EHMT2 overexpression has been reported in various types of cancer, including ovarian cancer and neuroblastoma, in relation to cell proliferation and metastasis. However, its role in NSCLC is not fully understood. In this study, we showed that EHMT2 gene expression was higher in NSCLC than normal lung tissue based on publicly available data. Inhibition of EHMT2 by BIX01294 (BIX) reduced cell viability of NSCLC cell lines via induction of autophagy. Through RNA sequencing analysis, we found that EHMT2 inhibition significantly affected the cholesterol biosynthesis pathway. BIX treatment directly induced the expression of SREBF2, which is a master regulator of cholesterol biosynthesis, by lowering H3K9me1 and H3K9me2 at the promoter. Treatment of a cholesterol biosynthesis inhibitor, 25-hydroxycholesterol (25-HC), partially recovered BIX-induced cell death by attenuating autophagy. Our data demonstrated that EHMT2 inhibition effectively induced cell death in NSCLC cells through altering cholesterol metabolism-dependent autophagy. Full article

(This article belongs to the Special Issue Cancer Metabolism—Metabolites Regulation of Oncogenic Signaling and Epigenetics)

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18 pages, 4352 KiB

Open AccessArticle

MCP-1/MCPIP-1 Signaling Modulates the Effects of IL-1β in Renal Cell Carcinoma through ER Stress-Mediated Apoptosis

by Chia-Huei Lee, Pin-Feng Hung, Shang-Chieh Lu, Hsuan-Lien Chung, Shang-Lun Chiang, Chun-Te Wu, Wei-Chun Chou and Chiao-Yin Sun

Int. J. Mol. Sci. 2019, 20(23), 6101; https://doi.org/10.3390/ijms20236101 - 3 Dec 2019

Cited by 18 | Viewed by 4925

Abstract

In renal cell carcinoma (RCC), interleukin (IL)-1β may be a pro-metastatic cytokine. However, we have not yet noted the clinical association between tumoral expression or serum level of IL-1β and RCC in our patient cohort. Herein, we investigate molecular mechanisms elicited by IL-1β in RCC. We found that IL-1β stimulates substantial monocyte chemoattractant protein (MCP)-1 production in RCC cells by activating NF-kB and AP-1. In our xenograft RCC model, intra-tumoral MCP-1 injection down-regulated Ki67 expression and reduced tumor size. Microarray analysis revealed that MCP-1 treatment altered protein-folding processes in RCC cells. MCP-1-treated RCC cells and xenograft tumors expressed MCP-1-induced protein (MCPIP) and molecules involved in endoplasmic reticulum (ER) stress-mediated apoptosis, namely C/EBP Homologous Protein (CHOP), protein kinase-like ER kinase (PERK), and calnexin (CNX). ER stress-mediated apoptosis in MCP-1-treated RCC cells was confirmed using Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) assay. Moreover, ectopic MCPIP expression increased PERK expression in Human embryonic kidney (HEK)293 cells. Our meta-analysis revealed that low MCP-1 levels reduce 1-year post-nephrectomy survival in patients with RCC. Immunohistochemistry indicated that in some RCC biopsy samples, the correlation between MCP-1 or MCPIP expression and tumor stages was inverse. Thus, MCP-1 and MCPIP potentially reduce the IL-1β-mediated oncogenic effect in RCC; our findings suggest that ER stress is a potential RCC treatment target. Full article

(This article belongs to the Special Issue Cancer Metabolism—Metabolites Regulation of Oncogenic Signaling and Epigenetics)

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9 pages, 2578 KiB

Open AccessArticle

USP14 Inhibition Regulates Tumorigenesis by Inducing Autophagy in Lung Cancer In Vitro

by Kyung Ho Han, Minseok Kwak, Tae Hyeong Lee, Min-soo Park, In-ho Jeong, Min Ji Kim, Jun-O Jin and Peter Chang-Whan Lee

Int. J. Mol. Sci. 2019, 20(21), 5300; https://doi.org/10.3390/ijms20215300 - 24 Oct 2019

Cited by 39 | Viewed by 4315

Abstract

The ubiquitin–proteasome system is an essential regulator of several cellular pathways involving oncogenes. Deubiquitination negatively regulates target proteins or substrates linked to both hereditary and sporadic forms of cancer. The deubiquitinating enzyme ubiquitin-specific protease 14 (USP14) is associated with proteasomes where it trims the ubiquitin chain on the substrate. Here, we found that USP14 is highly expressed in patients with lung cancer. We also demonstrated that USP14 inhibitors (IU1-47 and siRNA-USP14) significantly decreased cell proliferation, migration, and invasion in lung cancer. Remarkably, we found that USP14 negatively regulates lung tumorigenesis not only through apoptosis but also through the autophagy pathway. Our findings suggest that USP14 plays a crucial role in lung tumorigenesis and that USP14 inhibitors are potent drugs in lung cancer treatment. Full article

(This article belongs to the Special Issue Cancer Metabolism—Metabolites Regulation of Oncogenic Signaling and Epigenetics)

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16 pages, 2807 KiB

Open AccessArticle

IDH1^R132H Causes Resistance to HDAC Inhibitors by Increasing NANOG in Glioblastoma Cells

by Geon-Hee Kim, So Young Choi, Taek-In Oh, Sang-Yeon Kan, Hyeji Kang, Sujin Lee, Taerim Oh, Hyun Myung Ko and Ji-Hong Lim

Int. J. Mol. Sci. 2019, 20(11), 2679; https://doi.org/10.3390/ijms20112679 - 31 May 2019

Cited by 16 | Viewed by 4433

Abstract

The R132H mutation in isocitrate dehydrogenase 1 (IDH1^R132H) is commonly observed and associated with better survival in glioblastoma multiforme (GBM), a malignant brain tumor. However, the functional role of IDH1^R132H as a molecular target for GBM treatment is not completely understood. In this study, we found that the overexpression of IDH1^R132H suppresses cell growth, cell cycle progression and motility in U87MG glioblastoma cells. Based on cell viability and apoptosis assays, we found that IDH1^R132H-overexpressing U87MG and U373MG cells are resistant to the anti-cancer effect of histone deacetylase inhibitors (HDACi), such as trichostatin A (TSA), vorinostat (SAHA), and valproic acid. Octyl-(R)-2-hydroxyglutarate (Octyl-2HG), which is a membrane-permeable precursor form of the oncometabolite (R)-2-hydroxyglutarate (R-2HG) produced in IDH1-mutant tumor cells, significantly increased HDACi resistance in glioblastoma cells. Mechanistically, IDH1^R132H and Octyl-2HG enhanced the promoter activation of NANOG via increased H3K4-3Me, consequently increasing NANOG mRNA and protein expression. Indeed, HDACi resistance was attenuated in IDH1^R132H-expressing glioblastoma cells by the suppression of NANOG using small interfering RNAs. Furthermore, we found that AGI-5198, a selective inhibitor of IDH1^R132H, significantly attenuates HDACi resistance and NANOG expression IDH1^R132H-expressing glioblastoma cells. These results suggested that IDH1^R132H is a potential molecular target for HDACi-based therapy for GBM. Full article

(This article belongs to the Special Issue Cancer Metabolism—Metabolites Regulation of Oncogenic Signaling and Epigenetics)

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13 pages, 2297 KiB

Open AccessArticle

Methylation of SPARCL1 Is Associated with Oncologic Outcome of Advanced Upper Urinary Tract Urothelial Carcinoma

by Hao-Lun Luo, Po-Huang Chiang, Chun-Chieh Huang, Yu-Li Su, Min-Tse Sung, Eing-Mei Tsai, Chang-Shen Lin and Po-Hui Chiang

Int. J. Mol. Sci. 2019, 20(7), 1653; https://doi.org/10.3390/ijms20071653 - 3 Apr 2019

Cited by 13 | Viewed by 3352

Abstract

Advanced upper urinary tract urothelial carcinoma (UTUC) is often associated with poor oncologic outcomes. The secreted protein acidic and rich in cysteine-like 1 (SPARCL1) protein, belongs to the SPARC-related family of matricellular proteins. Much literature has been published describing the role of SPARCL1 in the prognosis many cancers. In this study, methylated promoter regions in high-grade and high-stage upper urinary urothelial tumours compared with normal urothelium were analyzed and revealed that SPARCL1 was the most significantly hypermethylated gene in UTUC tissues. Then we prospectively collected UTUC samples and adjacent normal urothelium for pyrosequencing validation, identifying significant CpG site methylation in UTUC tissues. In addition, SPARCL1 RNA levels were significantly lower in UTUC samples. Multivariate Cox regression analysis from 78 patients with solitary renal pelvic or ureteral pT3N0M0 urothelial carcinomas revealed that only negative SPARCL1 expression and nonpapillary tumour architecture were independently associated with systemic recurrence (p = 0.011 and 0.008, respectively). In vitro studies revealed that the behaviour of BFTC-909 cells was less aggressive and more sensitive to radiation or chemotherapy after SPARCL1 overexpression. Thus, SPARCL1 could be considered as a prognostic marker and help decision-making in clinical practice. Full article

(This article belongs to the Special Issue Cancer Metabolism—Metabolites Regulation of Oncogenic Signaling and Epigenetics)

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14 pages, 7455 KiB

Open AccessArticle

Role of SIRT-3, p-mTOR and HIF-1α in Hepatocellular Carcinoma Patients Affected by Metabolic Dysfunctions and in Chronic Treatment with Metformin

by Serena De Matteis, Emanuela Scarpi, Anna Maria Granato, Umberto Vespasiani-Gentilucci, Giuliano La Barba, Francesco Giuseppe Foschi, Erika Bandini, Martina Ghetti, Giorgia Marisi, Paola Cravero, Laura Gramantieri, Alessandro Cucchetti, Giorgio Ercolani, Daniele Santini, Giovanni Luca Frassineti, Luca Faloppi, Mario Scartozzi, Stefano Cascinu and Andrea Casadei-Gardini

Int. J. Mol. Sci. 2019, 20(6), 1503; https://doi.org/10.3390/ijms20061503 - 26 Mar 2019

Cited by 26 | Viewed by 4872

Abstract

The incidence of hepatocellular carcinoma deriving from metabolic dysfunctions has increased in the last years. Sirtuin- (SIRT-3), phospho-mammalian target of rapamycin (p-mTOR) and hypoxia-inducible factor- (HIF-1α) are involved in metabolism and cancer. However, their role in hepatocellular carcinoma (HCC) metabolism, drug resistance and progression remains unclear. This study aimed to better clarify the biological and clinical function of these markers in HCC patients, in relation to the presence of metabolic alterations, metformin therapy and clinical outcome. A total of 70 HCC patients were enrolled: 48 and 22 of whom were in early stage and advanced stage, respectively. The expression levels of the three markers were assessed by immunohistochemistry and summarized using descriptive statistics. SIRT-3 expression was higher in diabetic than non-diabetic patients, and in metformin-treated than insulin-treated patients. Interestingly, p-mTOR was higher in patients with metabolic syndrome than those with different etiology, and, similar to SIRT-3, in metformin-treated than insulin-treated patients. Moreover, our results describe a slight, albeit not significant, benefit of high SIRT-3 and a significant benefit of high nuclear HIF-1α expression in early-stage patients, whereas high levels of p-mTOR correlated with worse prognosis in advanced-stage patients. Our study highlighted the involvement of SIRT-3 and p-mTOR in metabolic dysfunctions that occur in HCC patients, and suggested SIRT-3 and HIF-1α as predictors of prognosis in early-stage HCC patients, and p-mTOR as target for the treatment of advanced-stage HCC. Full article

(This article belongs to the Special Issue Cancer Metabolism—Metabolites Regulation of Oncogenic Signaling and Epigenetics)

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16 pages, 1767 KiB

Open AccessArticle

Epigenetic Modifications of the Liver Tumor Cell Line HepG2 Increase Their Drug Metabolic Capacity

by Marc Ruoß, Georg Damm, Massoud Vosough, Lisa Ehret, Carl Grom-Baumgarten, Martin Petkov, Silvio Naddalin, Ruth Ladurner, Daniel Seehofer, Andreas Nussler and Sahar Sajadian

Int. J. Mol. Sci. 2019, 20(2), 347; https://doi.org/10.3390/ijms20020347 - 16 Jan 2019

Cited by 26 | Viewed by 6754

Abstract

Although human liver tumor cells have reduced metabolic functions as compared to primary human hepatocytes (PHH) they are widely used for pre-screening tests of drug metabolism and toxicity. The aim of the present study was to modify liver cancer cell lines in order to improve their drug-metabolizing activities towards PHH. It is well-known that epigenetics is strongly modified in tumor cells and that epigenetic regulators influence the expression and function of Cytochrome P450 (CYP) enzymes through altering crucial transcription factors responsible for drug-metabolizing enzymes. Therefore, we screened the epigenetic status of four different liver cancer cell lines (Huh7, HLE, HepG2 and AKN-1) which were reported to have metabolizing drug activities. Our results showed that HepG2 cells demonstrated the highest similarity compared to PHH. Thus, we modified the epigenetic status of HepG2 cells towards ‘normal’ liver cells by 5-Azacytidine (5-AZA) and Vitamin C exposure. Then, mRNA expression of Epithelial-mesenchymal transition (EMT) marker SNAIL and CYP enzymes were measured by PCR and determinate specific drug metabolites, associated with CYP enzymes by LC/MS. Our results demonstrated an epigenetic shift in HepG2 cells towards PHH after exposure to 5-AZA and Vitamin C which resulted in a higher expression and activity of specific drug metabolizing CYP enzymes. Finally, we observed that 5-AZA and Vitamin C led to an increased expression of Hepatocyte nuclear factor 4α (HNF4α) and E-Cadherin and a significant down regulation of Snail1 (SNAIL), the key transcriptional repressor of E-Cadherin. Our study shows, that certain phase I genes and their enzyme activities are increased by epigenetic modification in HepG2 cells with a concomitant reduction of EMT marker gene SNAIL. The enhancing of liver specific functions in hepatoma cells using epigenetic modifiers opens new opportunities for the usage of cell lines as a potential liver in vitro model for drug testing and development. Full article

(This article belongs to the Special Issue Cancer Metabolism—Metabolites Regulation of Oncogenic Signaling and Epigenetics)

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Review

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17 pages, 785 KiB

Open AccessReview

Glutamine Addiction and Therapeutic Strategies in Lung Cancer

by Karolien Vanhove, Elien Derveaux, Geert-Jan Graulus, Liesbet Mesotten, Michiel Thomeer, Jean-Paul Noben, Wanda Guedens and Peter Adriaensens

Int. J. Mol. Sci. 2019, 20(2), 252; https://doi.org/10.3390/ijms20020252 - 10 Jan 2019

Cited by 89 | Viewed by 10266

Abstract

Lung cancer cells are well-documented to rewire their metabolism and energy production networks to support rapid survival and proliferation. This metabolic reorganization has been recognized as a hallmark of cancer. The increased uptake of glucose and the increased activity of the glycolytic pathway have been extensively described. However, over the past years, increasing evidence has shown that lung cancer cells also require glutamine to fulfill their metabolic needs. As a nitrogen source, glutamine contributes directly (or indirectly upon conversion to glutamate) to many anabolic processes in cancer, such as the biosynthesis of amino acids, nucleobases, and hexosamines. It plays also an important role in the redox homeostasis, and last but not least, upon conversion to α-ketoglutarate, glutamine is an energy and anaplerotic carbon source that replenishes tricarboxylic acid cycle intermediates. The latter is generally indicated as glutaminolysis. In this review, we explore the role of glutamine metabolism in lung cancer. Because lung cancer is the leading cause of cancer death with limited curative treatment options, we focus on the potential therapeutic approaches targeting the glutamine metabolism in cancer. Full article

(This article belongs to the Special Issue Cancer Metabolism—Metabolites Regulation of Oncogenic Signaling and Epigenetics)

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14 pages, 1438 KiB

Open AccessReview

Targeting Mitochondria for Treatment of Chemoresistant Ovarian Cancer

by Edith Emmings, Sally Mullany, Zenas Chang, Charles N. Landen, Jr., Stig Linder and Martina Bazzaro

Int. J. Mol. Sci. 2019, 20(1), 229; https://doi.org/10.3390/ijms20010229 - 8 Jan 2019

Cited by 80 | Viewed by 13079

Abstract

Ovarian cancer is the leading cause of death from gynecologic malignancy in the Western world. This is due, in part, to the fact that despite standard treatment of surgery and platinum/paclitaxel most patients recur with ultimately chemoresistant disease. Ovarian cancer is a unique form of solid tumor that develops, metastasizes and recurs in the same space, the abdominal cavity, which becomes a unique microenvironment characterized by ascites, hypoxia and low glucose levels. It is under these conditions that cancer cells adapt and switch to mitochondrial respiration, which becomes crucial to their survival, and therefore an ideal metabolic target for chemoresistant ovarian cancer. Importantly, independent of microenvironmental factors, mitochondria spatial redistribution has been associated to both tumor metastasis and chemoresistance in ovarian cancer while specific sets of genetic mutations have been shown to cause aberrant dependence on mitochondrial pathways in the most aggressive ovarian cancer subtypes. In this review we summarize on targeting mitochondria for treatment of chemoresistant ovarian cancer and current state of understanding of the role of mitochondria respiration in ovarian cancer. We feel this is an important and timely topic given that ovarian cancer remains the deadliest of the gynecological diseases, and that the mitochondrial pathway has recently emerged as critical in sustaining solid tumor progression. Full article

(This article belongs to the Special Issue Cancer Metabolism—Metabolites Regulation of Oncogenic Signaling and Epigenetics)

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