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      Sphingolipid metabolism and drug resistance in ovarian cancer

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          Abstract

          Despite progress in understanding molecular aberrations that contribute to the development and progression of ovarian cancer, virtually all patients succumb to drug resistant disease at relapse. Emerging data implicate bioactive sphingolipids and regulation of sphingolipid metabolism as components of response to chemotherapy or development of resistance. Increases in cytosolic ceramide induce apoptosis in response to therapy with multiple classes of chemotherapeutic agents. Aberrations in sphingolipid metabolism that accelerate the catabolism of ceramide or that prevent the production and accumulation of ceramide contribute to resistance to standard of care platinum- and taxane-based agents. The aim of this review is to highlight current literature and research investigating the influence of the sphingolipids and enzymes that comprise the sphingosine-1-phosphate pathway on the progression of ovarian cancer. The focus of the review is on the utility of sphingolipid-centric therapeutics as a mechanism to circumvent drug resistance in this tumor type.

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          Ovarian cancer

          Gordon C Jayson, Elise C Kohn, Henry C Kitchener … (2014)
          Epithelial ovarian cancer is the commonest cause of gynaecological cancer-associated death. The disease typically presents in postmenopausal women, with a few months of abdominal pain and distension. Most women have advanced disease (International Federation of Gynecology and Obstetrics [FIGO] stage III), for which the standard of care remains surgery and platinum-based cytotoxic chemotherapy. Although this treatment can be curative for most patients with early stage disease, most women with advanced disease will develop many episodes of recurrent disease with progressively shorter disease-free intervals. These episodes culminate in chemoresistance and ultimately bowel obstruction, the most frequent cause of death. For women whose disease continues to respond to platinum-based drugs, the disease can often be controlled for 5 years or more. Targeted treatments such as antiangiogenic drugs or poly (ADP-ribose) polymerase inhibitors offer potential for improved survival. The efficacy of screening, designed to detect the disease at an earlier and curable stage remains unproven, with key results expected in 2015. Copyright © 2014 Elsevier Ltd. All rights reserved.
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            Sphingolipids and their metabolism in physiology and disease

            Yusuf Hannun, Lina M. Obeid (2017)
            Studies of bioactive lipids in general and sphingolipids in particular have intensified over the past several years, revealing an unprecedented and unanticipated complexity of the lipidome and its many functions, which rivals, if not exceeds, that of the genome or proteome. These results highlight critical roles for bioactive sphingolipids in most, if not all, major cell biological responses, including all major cell signalling pathways, and they link sphingolipid metabolism to key human diseases. Nevertheless, the fairly nascent field of bioactive sphingolipids still faces challenges in its biochemical and molecular underpinnings, including defining the molecular mechanisms of pathway and enzyme regulation, the study of lipid-protein interactions and the development of cellular probes, suitable biomarkers and therapeutic approaches.
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              Sphingosine-1-phosphate: an enigmatic signalling lipid.

              Sarah Spiegel, Sheldon Milstien (2003)
              The evolutionarily conserved actions of the sphingolipid metabolite, sphingosine-1-phosphate (S1P), in yeast, plants and mammals have shown that it has important functions. In higher eukaryotes, S1P is the ligand for a family of five G-protein-coupled receptors. These S1P receptors are differentially expressed, coupled to various G proteins, and regulate angiogenesis, vascular maturation, cardiac development and immunity, and are important for directed cell movement.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101738710
                Journal ID (pubmed-jr-id): 48234
                Journal ID (nlm-ta): Cancer Drug Resist
                Journal ID (iso-abbrev): Cancer Drug Resist
                Title: Cancer drug resistance (Alhambra, Calif.)
                ISSN (Electronic): 2578-532X
                Publication date Nihms-submitted: 16 December 2019
                Publication date (Electronic): 19 September 2018
                Publication date (Print): 2018
                Publication date PMC-release: 30 December 2019
                Volume: 1
                Pages: 181-197
                Affiliations
                Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
                Author notes

                Authors’ contributions

                Concepted: Kreitzburg KM, van Waardenburg RCAM, Yoon KJ

                Designed: Kreitzburg KM, Yoon KJ

                Wrote (first draft): Kreitzburg KM

                Wrote, reviewed, discussed, edited, and revised: Kreitzburg KM, van Waardenburg RCAM, Yoon KJ

                Correspondence to: Dr. Karina J. Yoon, Department of Pharmacology and Toxicology, University of Alabama at Birmingham, 1670 University Blvd, Birmingham, AL 35294, USA. kyoon@ 123456uab.edu
                Article
                Manuscript ID: NIHMS1063332
                DOI: 10.20517/cdr.2018.06
                PMC ID: 6936734
                PubMed ID: 31891125
                SO-VID: 6ce1a375-6415-44f1-bcbf-708ce41d9355
                License:

                This article is licensed under a Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                Categories
                Subject: Article

                Keywords: ovarian cancer,drug-resistance,ceramide,sphingosine-1-phosphate,sphingolipid metabolism
                Data availability:
                Keywords: ovarian cancer, drug-resistance, ceramide, sphingosine-1-phosphate, sphingolipid metabolism

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