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Open AccessArticle

Cholesterol Homeostasis Modulates Platinum Sensitivity in Human Ovarian Cancer

1
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy
2
CRG - Centre for Genomic Regulation, 08003 Barcelona, Spain
3
Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy
4
Institute Experimental Endocrinology and Oncology “Gaetano Salvatore”, National Research Council (IEOS-CNR), 80131 Naples, Italy
5
Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, 7100 Foggia, Italy
*
Authors to whom correspondence should be addressed.
Cells 2020, 9(4), 828; https://doi.org/10.3390/cells9040828
Received: 31 January 2020 / Revised: 19 March 2020 / Accepted: 23 March 2020 / Published: 30 March 2020
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Ovarian Cancer)
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. View Full-Text
Keywords: ovarian cancer; TRAP1; cholesterol homeostasis; platinum resistance ovarian cancer; TRAP1; cholesterol homeostasis; platinum resistance
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Criscuolo, D.; Avolio, R.; Calice, G.; Laezza, C.; Paladino, S.; Navarra, G.; Maddalena, F.; Crispo, F.; Pagano, C.; Bifulco, M.; Landriscina, M.; Matassa, D.S.; Esposito, F. Cholesterol Homeostasis Modulates Platinum Sensitivity in Human Ovarian Cancer. Cells 2020, 9, 828.

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