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Cancers
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Metabolism in Ovarian Cancer
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Metabolism in Ovarian Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (15 December 2021) | Viewed by 21496

Special Issue Editors

Dr. Ramandeep Rattan

E-Mail Website
Guest Editor
Division of Gynecology Oncology, Department of Women's Health Services, Henry Ford Health System, Detroit, MI 48202, USA
Interests: ovarian cancer metabolism; bioenergetic adaptations; AMPK; caloric restriction
Dr. Gil Mor

E-Mail Website
Guest Editor
Department of Obstetrics and Gynecology, C.S. Mott Center for Human Growth and Development, Wayne State University, Detroit, MI 48201, USA
Interests: ovarian cancer; epithelial mesenchymal transition; immune modulation; immune therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Metabolic reprogramming is recognized as a hallmark of cancer cells. Almost all oncogenes regulate some aspect of metabolism and aid the tumor cells in altering their metabolism, which enables them to overcome growth constraints, resulting in successful growth and metastasis.

Due to its peritoneal placement, ovarian cancer is exposed to a unique microenvironment enriched in pro-inflammatory factors and bioactive lipids. Studies show that ovarian cancer cells undergo lipid/adipose-mediated metabolic adaptations to facilitate metastasis, acquire a flexible energy metabolism to escape chemotherapy, and retain stem-cell-like characteristics.

However, the complexity and acquisition of metabolic adaptations and the ensuing cellular fitness is still unknown. Understanding the contribution of multiple metabolic processes regulated by nutrients and cellular components of the micro-environment can lead to the development of targeted agents and multi-targeting strategies to repress ovarian tumor progression.

This special issue will highlight the current state in ovarian cancer metabolism, metabolic inhibitors, and future directions for improving ovarian cancer outcomes.

Dr. Ramandeep Rattan
Dr. Gil Mor
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • chemotherapy
  • epithelial mesenchymal transition
  • immune metabolism
  • chemoresistance

Published Papers (7 papers)

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Research

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19 pages, 1906 KiB  
Article
Pharmacological Inhibition of Lipid Import and Transport Proteins in Ovarian Cancer
by Lisa Lemberger, Renate Wagner, Gerwin Heller, Dietmar Pils and Thomas W. Grunt
Cancers 2022, 14(23), 6004; https://doi.org/10.3390/cancers14236004 - 5 Dec 2022
Cited by 5 | Viewed by 1761
Abstract
Ovarian cancer (OC) is the most lethal gynecological malignancy with a 5-year survival rate of 49%. This is caused by late diagnosis when cells have already metastasized into the peritoneal cavity and to the omentum. OC progression is dependent on the availability of [...] Read more.
Ovarian cancer (OC) is the most lethal gynecological malignancy with a 5-year survival rate of 49%. This is caused by late diagnosis when cells have already metastasized into the peritoneal cavity and to the omentum. OC progression is dependent on the availability of high-energy lipids/fatty acids (FA) provided by endogenous de novo biosynthesis and/or through import from the microenvironment. The blockade of these processes may thus represent powerful strategies against OC. While this has already been shown for inhibition of FA/lipid biosynthesis, evidence of the role of FA/lipid import/transport is still sparse. Therefore, we treated A2780 and SKOV3 OC cells with inhibitors of the lipid uptake proteins fatty acid translocase/cluster of differentiation 36 (FAT/CD36) and low-density lipoprotein (LDL) receptor (LDLR), as well as intracellular lipid transporters of the fatty acid-binding protein (FABP) family, fatty acid transport protein-2 (FATP2/SLC27A2), and ADP-ribosylation factor 6 (ARF6), which are overexpressed in OC. Proliferation was determined by formazan dye labeling/photometry and cell counting. Cell cycle analysis was performed by propidium iodide (PI) staining, and apoptosis was examined by annexin V/PI and active caspase 3 labeling and flow cytometry. RNA-seq data revealed altered stress and metabolism pathways. Overall, the small molecule inhibitors of lipid handling proteins BMS309403, HTS01037, NAV2729, SB-FI-26, and sulfosuccinimidyl oleate (SSO) caused a drug-specific, dose-/time-dependent inhibition of FA/LDL uptake, associated with reduced proliferation, cell cycle arrest, and apoptosis. Our findings indicate that OC cells are very sensitive to lipid deficiency. This dependency should be exploited for development of novel strategies against OC. Full article
(This article belongs to the Special Issue Metabolism in Ovarian Cancer)
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17 pages, 3099 KiB  
Article
Atovaquone: An Inhibitor of Oxidative Phosphorylation as Studied in Gynecologic Cancers
by Arvinder Kapur, Pooja Mehta, Aaron D Simmons, Spencer S. Ericksen, Geeta Mehta, Sean P. Palecek, Mildred Felder, Zach Stenerson, Amruta Nayak, Jose Maria Ayuso Dominguez, Manish Patankar and Lisa M. Barroilhet
Cancers 2022, 14(9), 2297; https://doi.org/10.3390/cancers14092297 - 5 May 2022
Cited by 20 | Viewed by 2986
Abstract
Oxidative phosphorylation is an active metabolic pathway in cancer. Atovaquone is an oral medication that inhibits oxidative phosphorylation and is FDA-approved for the treatment of malaria. We investigated its potential anti-cancer properties by measuring cell proliferation in 2D culture. The clinical formulation of [...] Read more.
Oxidative phosphorylation is an active metabolic pathway in cancer. Atovaquone is an oral medication that inhibits oxidative phosphorylation and is FDA-approved for the treatment of malaria. We investigated its potential anti-cancer properties by measuring cell proliferation in 2D culture. The clinical formulation of atovaquone, Mepron, was given to mice with ovarian cancers to monitor its effects on tumor and ascites. Patient-derived cancer stem-like cells and spheroids implanted in NSG mice were treated with atovaquone. Atovaquone inhibited the proliferation of cancer cells and ovarian cancer growth in vitro and in vivo. The effect of atovaquone on oxygen radicals was determined using flow and imaging cytometry. The oxygen consumption rate (OCR) in adherent cells was measured using a Seahorse XFe96 Extracellular Flux Analyzer. Oxygen consumption and ATP production were inhibited by atovaquone. Imaging cytometry indicated that the majority of the oxygen radical flux triggered by atovaquone occurred in the mitochondria. Atovaquone decreased the viability of patient-derived cancer stem-like cells and spheroids implanted in NSG mice. NMR metabolomics showed shifts in glycolysis, citric acid cycle, electron transport chain, phosphotransfer, and metabolism following atovaquone treatment. Our studies provide the mechanistic understanding and preclinical data to support the further investigation of atovaquone’s potential as a gynecologic cancer therapeutic. Full article
(This article belongs to the Special Issue Metabolism in Ovarian Cancer)
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28 pages, 55690 KiB  
Article
Divergent Metabolic Effects of Metformin Merge to Enhance Eicosapentaenoic Acid Metabolism and Inhibit Ovarian Cancer In Vivo
by Mary P. Udumula, Laila M. Poisson, Indrani Dutta, Nivedita Tiwari, Seongho Kim, Jasdeep Chinna-Shankar, Ghassan Allo, Sharif Sakr, Miriana Hijaz, Adnan R. Munkarah, Shailendra Giri and Ramandeep Rattan
Cancers 2022, 14(6), 1504; https://doi.org/10.3390/cancers14061504 - 15 Mar 2022
Cited by 4 | Viewed by 2657
Abstract
Metformin is being actively repurposed for the treatment of gynecologic malignancies including ovarian cancer. We investigated if metformin induces analogous metabolic changes across ovarian cancer cells. Functional metabolic analysis showed metformin caused an immediate and sustained decrease in oxygen consumption while increasing glycolysis [...] Read more.
Metformin is being actively repurposed for the treatment of gynecologic malignancies including ovarian cancer. We investigated if metformin induces analogous metabolic changes across ovarian cancer cells. Functional metabolic analysis showed metformin caused an immediate and sustained decrease in oxygen consumption while increasing glycolysis across A2780, C200, and SKOV3ip cell lines. Untargeted metabolomics showed metformin to have differential effects on glycolysis and TCA cycle metabolites, while consistent increased fatty acid oxidation intermediates were observed across the three cell lines. Metabolite set enrichment analysis showed alpha-linolenic/linoleic acid metabolism as being most upregulated. Downstream mediators of the alpha-linolenic/linoleic acid metabolism, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were abundant in all three cell lines. EPA was more effective in inhibiting SKOV3 and CaOV3 xenografts, which correlated with inhibition of inflammatory markers and indicated a role for EPA-derived specialized pro-resolving mediators such as Resolvin E1. Thus, modulation of the metabolism of omega-3 fatty acids and their anti-inflammatory signaling molecules appears to be one of the common mechanisms of metformin’s antitumor activity. The distinct metabolic signature of the tumors may indicate metformin response and aid the preclinical and clinical interpretation of metformin therapy in ovarian and other cancers. Full article
(This article belongs to the Special Issue Metabolism in Ovarian Cancer)
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22 pages, 3558 KiB  
Article
Metabolic Reprogramming of Ovarian Cancer Spheroids during Adhesion
by Stephanie L. E. Compton, Joseph P. Grieco, Benita Gollamudi, Eric Bae, Jennifer H. Van Mullekom and Eva M. Schmelz
Cancers 2022, 14(6), 1399; https://doi.org/10.3390/cancers14061399 - 9 Mar 2022
Cited by 5 | Viewed by 2774
Abstract
Ovarian cancer remains a deadly disease and its recurrence disease is due in part to the presence of disseminating ovarian cancer aggregates not removed by debulking surgery. During dissemination in a dynamic ascitic environment, the spheroid cells’ metabolism is characterized by low respiration [...] Read more.
Ovarian cancer remains a deadly disease and its recurrence disease is due in part to the presence of disseminating ovarian cancer aggregates not removed by debulking surgery. During dissemination in a dynamic ascitic environment, the spheroid cells’ metabolism is characterized by low respiration and fragmented mitochondria, a metabolic phenotype that may not support secondary outgrowth after adhesion. Here, we investigated how adhesion affects cellular respiration and substrate utilization of spheroids mimicking early stages of secondary metastasis. Using different glucose and oxygen levels, we investigated cellular metabolism at early time points of adherence (24 h and less) comparing slow and fast-developing disease models. We found that adhesion over time showed changes in cellular energy metabolism and substrate utilization, with a switch in the utilization of mostly glutamine to glucose but no changes in fatty acid oxidation. Interestingly, low glucose levels had less of an impact on cellular metabolism than hypoxia. A resilience to culture conditions and the capacity to utilize a broader spectrum of substrates more efficiently distinguished the highly aggressive cells from the cells representing slow-developing disease, suggesting a flexible metabolism contributes to the stem-like properties. These results indicate that adhesion to secondary sites initiates a metabolic switch in the oxidation of substrates that could support outgrowth and successful metastasis. Full article
(This article belongs to the Special Issue Metabolism in Ovarian Cancer)
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20 pages, 1383 KiB  
Article
Evaluating Targeted Therapies in Ovarian Cancer Metabolism: Novel Role for PCSK9 and Second Generation mTOR Inhibitors
by Dafne Jacome Sanz, Juuli Raivola, Hanna Karvonen, Mariliina Arjama, Harlan Barker, Astrid Murumägi and Daniela Ungureanu
Cancers 2021, 13(15), 3727; https://doi.org/10.3390/cancers13153727 - 24 Jul 2021
Cited by 12 | Viewed by 3457
Abstract
Background: Dysregulated lipid metabolism is emerging as a hallmark in several malignancies, including ovarian cancer (OC). Specifically, metastatic OC is highly dependent on lipid-rich omentum. We aimed to investigate the therapeutic value of targeting lipid metabolism in OC. For this purpose, we studied [...] Read more.
Background: Dysregulated lipid metabolism is emerging as a hallmark in several malignancies, including ovarian cancer (OC). Specifically, metastatic OC is highly dependent on lipid-rich omentum. We aimed to investigate the therapeutic value of targeting lipid metabolism in OC. For this purpose, we studied the role of PCSK9, a cholesterol-regulating enzyme, in OC cell survival and its downstream signaling. We also investigated the cytotoxic efficacy of a small library of metabolic (n = 11) and mTOR (n = 10) inhibitors using OC cell lines (n = 8) and ex vivo patient-derived cell cultures (PDCs, n = 5) to identify clinically suitable drug vulnerabilities. Targeting PCSK9 expression with siRNA or PCSK9 specific inhibitor (PF-06446846) impaired OC cell survival. In addition, overexpression of PCSK9 induced robust AKT phosphorylation along with increased expression of ERK1/2 and MEK1/2, suggesting a pro-survival role of PCSK9 in OC cells. Moreover, our drug testing revealed marked differences in cytotoxic responses to drugs targeting metabolic pathways of high-grade serous ovarian cancer (HGSOC) and low-grade serous ovarian cancer (LGSOC) PDCs. Our results show that targeting PCSK9 expression could impair OC cell survival, which warrants further investigation to address the dependency of this cancer on lipogenesis and omental metastasis. Moreover, the differences in metabolic gene expression and drug responses of OC PDCs indicate the existence of a metabolic heterogeneity within OC subtypes, which should be further explored for therapeutic improvements. Full article
(This article belongs to the Special Issue Metabolism in Ovarian Cancer)
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Review

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15 pages, 1279 KiB  
Review
Regulatory Role of the Adipose Microenvironment on Ovarian Cancer Progression
by Hussein Chehade, Roslyn Tedja, Harry Ramos, Tejeshwar Singh Bawa, Nicholas Adzibolosu, Radhika Gogoi, Gil Mor and Ayesha B. Alvero
Cancers 2022, 14(9), 2267; https://doi.org/10.3390/cancers14092267 - 1 May 2022
Cited by 9 | Viewed by 3130
Abstract
The tumor microenvironment of ovarian cancer is the peritoneal cavity wherein adipose tissue is a major component. The role of the adipose tissue in support of ovarian cancer progression has been elucidated in several studies from the past decades. The adipocytes, in particular, [...] Read more.
The tumor microenvironment of ovarian cancer is the peritoneal cavity wherein adipose tissue is a major component. The role of the adipose tissue in support of ovarian cancer progression has been elucidated in several studies from the past decades. The adipocytes, in particular, are a major source of factors, which regulate all facets of ovarian cancer progression such as acquisition of chemoresistance, enhanced metastatic potential, and metabolic reprogramming. In this review, we summarize the relevant studies, which highlight the role of adipocytes in ovarian cancer progression and offer insights into unanswered questions and possible future directions of research. Full article
(This article belongs to the Special Issue Metabolism in Ovarian Cancer)
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21 pages, 744 KiB  
Review
Folate Transport and One-Carbon Metabolism in Targeted Therapies of Epithelial Ovarian Cancer
by Adrianne Wallace-Povirk, Zhanjun Hou, Md. Junayed Nayeen, Aleem Gangjee and Larry H. Matherly
Cancers 2022, 14(1), 191; https://doi.org/10.3390/cancers14010191 - 31 Dec 2021
Cited by 13 | Viewed by 3297
Abstract
New therapies are urgently needed for epithelial ovarian cancer (EOC), the most lethal gynecologic malignancy. To identify new approaches for targeting EOC, metabolic vulnerabilities must be discovered and strategies for the selective delivery of therapeutic agents must be established. Folate receptor (FR) α [...] Read more.
New therapies are urgently needed for epithelial ovarian cancer (EOC), the most lethal gynecologic malignancy. To identify new approaches for targeting EOC, metabolic vulnerabilities must be discovered and strategies for the selective delivery of therapeutic agents must be established. Folate receptor (FR) α and the proton-coupled folate transporter (PCFT) are expressed in the majority of EOCs. FRβ is expressed on tumor-associated macrophages, a major infiltrating immune population in EOC. One-carbon (C1) metabolism is partitioned between the cytosol and mitochondria and is important for the synthesis of nucleotides, amino acids, glutathione, and other critical metabolites. Novel inhibitors are being developed with the potential for therapeutic targeting of tumors via FRs and the PCFT, as well as for inhibiting C1 metabolism. In this review, we summarize these exciting new developments in targeted therapies for both tumors and the tumor microenvironment in EOC. Full article
(This article belongs to the Special Issue Metabolism in Ovarian Cancer)
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