Cholesterol Homeostasis Modulates Platinum Sensitivity in Human 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 ser...
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MDPI AG
2020-03-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/9/4/828 |
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| author | Daniela Criscuolo Rosario Avolio Giovanni Calice Chiara Laezza Simona Paladino Giovanna Navarra Francesca Maddalena Fabiana Crispo Cristina Pagano Maurizio Bifulco Matteo Landriscina Danilo Swann Matassa Franca Esposito |
| author_facet | Daniela Criscuolo Rosario Avolio Giovanni Calice Chiara Laezza Simona Paladino Giovanna Navarra Francesca Maddalena Fabiana Crispo Cristina Pagano Maurizio Bifulco Matteo Landriscina Danilo Swann Matassa Franca Esposito |
| author_sort | Daniela Criscuolo |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T20:47:55Z |
| format | Article |
| id | doaj.art-79167669a532495ca781726e9c85ae30 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T20:47:55Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-79167669a532495ca781726e9c85ae302023-11-19T20:10:23ZengMDPI AGCells2073-44092020-03-019482810.3390/cells9040828Cholesterol Homeostasis Modulates Platinum Sensitivity in Human Ovarian CancerDaniela Criscuolo0Rosario Avolio1Giovanni Calice2Chiara Laezza3Simona Paladino4Giovanna Navarra5Francesca Maddalena6Fabiana Crispo7Cristina Pagano8Maurizio Bifulco9Matteo Landriscina10Danilo Swann Matassa11Franca Esposito12Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, ItalyCRG - Centre for Genomic Regulation, 08003 Barcelona, SpainLaboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, ItalyInstitute Experimental Endocrinology and Oncology “Gaetano Salvatore”, National Research Council (IEOS-CNR), 80131 Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, ItalyLaboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, ItalyLaboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, ItalyLaboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, ItalyDespite 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.https://www.mdpi.com/2073-4409/9/4/828ovarian cancerTRAP1cholesterol homeostasisplatinum resistance |
| spellingShingle | Daniela Criscuolo Rosario Avolio Giovanni Calice Chiara Laezza Simona Paladino Giovanna Navarra Francesca Maddalena Fabiana Crispo Cristina Pagano Maurizio Bifulco Matteo Landriscina Danilo Swann Matassa Franca Esposito Cholesterol Homeostasis Modulates Platinum Sensitivity in Human Ovarian Cancer Cells ovarian cancer TRAP1 cholesterol homeostasis platinum resistance |
| title | Cholesterol Homeostasis Modulates Platinum Sensitivity in Human Ovarian Cancer |
| title_full | Cholesterol Homeostasis Modulates Platinum Sensitivity in Human Ovarian Cancer |
| title_fullStr | Cholesterol Homeostasis Modulates Platinum Sensitivity in Human Ovarian Cancer |
| title_full_unstemmed | Cholesterol Homeostasis Modulates Platinum Sensitivity in Human Ovarian Cancer |
| title_short | Cholesterol Homeostasis Modulates Platinum Sensitivity in Human Ovarian Cancer |
| title_sort | cholesterol homeostasis modulates platinum sensitivity in human ovarian cancer |
| topic | ovarian cancer TRAP1 cholesterol homeostasis platinum resistance |
| url | https://www.mdpi.com/2073-4409/9/4/828 |
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