Cholesterol homeostasis modulates platinum sensitivity in human ovarian cancer

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• dc.contributor.author Criscuolo, Daniela
• dc.contributor.author Avolio, Rosario
• dc.contributor.author Calice, Giovanni
• dc.contributor.author Laezza, Chiara
• dc.contributor.author Paladino, Simona
• dc.contributor.author Navarra, Giovanna
• dc.contributor.author Maddalena, Francesca
• dc.contributor.author Crispo, Fabiana
• dc.contributor.author Pagano, Cristina
• dc.contributor.author Bifulco, Maurizio
• dc.contributor.author Landriscina, Matteo
• dc.contributor.author Matassa, Danilo Swann
• dc.contributor.author Esposito, Franca
• dc.date.accessioned 2020-05-07T11:02:47Z
• dc.date.available 2020-05-07T11:02:47Z
• dc.date.issued 2020
• dc.description.abstract Despite initial chemotherapy response, ovarian cancer is the deadliest gynecologic cancer, due to frequent relapse and onset of drug resistance. To date, there is no affordable diagnostic/prognostic biomarker for early detection of the disease. However, it has been recently shown that high grade serous ovarian cancers show peculiar oxidative metabolism, which is in turn responsible for inflammatory response and drug resistance. The molecular chaperone TRAP1 plays pivotal roles in such metabolic adaptations, due to the involvement in the regulation of mitochondrial respiration. Here, we show that platinum-resistant ovarian cancer cells also show reduced cholesterol biosynthesis, and mostly rely on the uptake of exogenous cholesterol for their needs. Expression of FDPS and OSC, enzymes involved in cholesterol synthesis, are decreased both in drug-resistant cells and upon TRAP1 silencing, whereas the expression of LDL receptor, the main mediator of extracellular cholesterol uptake, is increased. Strikingly, treatment with statins to inhibit cholesterol synthesis reduces cisplatin-induced apoptosis, whereas silencing of LIPG, an enzyme involved in lipid metabolism, or withdrawal of lipids from the culture medium, increases sensitivity to the drug. These results suggest caveats for the use of statins in ovarian cancer patients and highlights the importance of lipid metabolism in ovarian cancer treatment.
• dc.description.sponsorship This research was funded by POR CAMPANIA FESR 2014/2020 [project “SATIN” (Sviluppo di Approcci Terapeutici INnovativi per patologie neoplastiche resistenti ai trattamenti)]
• dc.format.mimetype application/pdf
• dc.identifier.citation Criscuolo D, Avolio R, Calice G, Laezza C, Paladino S, Navarra G et al. Cholesterol homeostasis modulates platinum sensitivity in human ovarian cancer. Cells. 2020 Mar 30; 9(4). pii: E828. DOI: 10.3390/cells9040828
• dc.identifier.doi http://dx.doi.org/10.3390/cells9040828
• dc.identifier.issn 2073-4409
• dc.identifier.uri http://hdl.handle.net/10230/44448
• dc.language.iso eng
• dc.publisher MDPI
• dc.relation.ispartof Cells. 2020 Mar 30; 9(4). pii: E828
• dc.rights © 2020 by Daniela Criscuolo et al. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.other Colesterol
• dc.subject.other Homeòstasi
• dc.subject.other Ovaris -- Càncer
• dc.title Cholesterol homeostasis modulates platinum sensitivity in human ovarian cancer
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion