Cholesterol Homeostasis Modulates Platinum Sensitivity in Human Ovarian Cancer

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.

Influence of cholesterol on cancer progression and therapy

“…However, few reports suggest cancer-promoting or chemoresistant effect on statin treatment [207 , 208] , (209). Low dose treatment of statin promotes its aggressiveness in prostate cancer [208] , likewise treatment of lovastatin in ovarian cancer decreases chemosensitivity towards platinum drugs [209] . Interestingly, in human subjects’ use of statin particularly simvastatin and atorvastatin not only reduce the risk of mortality but also increases survival among pancreatic cancer patients [210] , [211] , [212] .…”

“…In hepatocellular carcinoma cells, it has been shown that 7-Ketocholesterol (7-KC) up-regulates the expression of P-glycoprotein (P-gp) through PI3K/mTOR signaling thereby diminishing the efficacy of doxorubicin [230] . Studies in chemoresistant ovarian cancer cells show more cholesterol uptake via up-regulation of LDLR and a decrease in endogenous cholesterol biosynthesis through downregulation of enzymes involve in cholesterol biosynthesis i.e., Farnesyl Diphosphate Synthase (FDPS) and oxidosqualene cyclase (OSC) [209] .…”

“… Low dose treatment of simvastatin increases the aggressiveness of prostate cancer in mice models. [208] 2 Ovarian Cisplatin, Paclitaxel in vitro & Clinical PA-1, OVCAR-3, SKOV-3 cells Cholesterol increases expression of MDR1 through LXRɑ/β activation and imparts chemoresistance of cisplatin and paclitaxel [25] 3 Ovarian Cisplatin in vitro A2780 cell SREBP2 imparts cisplatin resistance via upregulation of LDLR, FDFT1, and HMGCR in A2780 cell [254] 4 Ovarian Cisplatin, Lovastatin in vitro PEA1, PEA2, PEO14 cells Inhibition of cholesterol biosynthesis with statin increases cisplatin chemoresistance in ovarian cancer [209] 5 Chronic myelogenous leukemia Imatinib in vitro K562R (imatinib resistant) cell A high level of cholesterol ester accumulation is associated with resistance to imatinib in chronic myelogenous leukemia cells [226] 6 Lung Cisplatin, Carboplatin,Oxaliplatin,Cholesterol in vitro & Clinical A549 cell,Patient sample Pretreatment of cholesterol increases the expression of ABCG2 which imparts chemoresistance to platinum-based drugs. [229] 7 Hepato-cellular Carcinoma Doxorubicin, in vitro Huh-7, HepG2 cells 7-Ketocholesterol regulate P-gp through PI3K/mTOR signaling and decreases the efficacy of Doxorubicin [230] 8 Hepato-cellular carcinoma Sorafenib in vitro HepG2, HUH7 cells Pre-treatment of LDLc decreases HCC cell death from sorafenib.…”

Identification and Development of Subtypes With Poor Prognosis in Pan-Gynecological Cancer Based on Gene Expression in the Glycolysis-Cholesterol Synthesis Axis

“…Cholesterol homeostasis plays an important role in the progression of cancer. In ovarian cancer, cholesterol homeostasis may modulate the sensitivity of ovarian cancer patients to platinum-based drugs ( 42 ). Our results suggested that cholesterol-related genes may be involved in drug resistance through cholesterol homeostasis, fatty acid metabolism, and other pathways in gynecological pan-cancer, but these are rarely studied in cervical and endometrial cancers.…”

IDH1 Targeting as a New Potential Option for Intrahepatic Cholangiocarcinoma Treatment—Current State and Future Perspectives

“…However, this cancer is highly chemoresistant and, at present, no second-line therapy with established benefits is available, even though several studies were carried out for this purpose [ 13 , 14 , 15 , 16 , 17 ]. Chemoresistance is the major cause of treatment failure in this setting and is often caused by the activation of several anti-apoptotic pathways [ 18 , 19 , 20 , 21 ], which may act alone or synergistically to sustain cancer cell escape from cytotoxic or cytostatic effects of anticancer agents. Certainly, a better knowledge and/or comprehension of complex mechanisms responsible for drug resistance may improve the management of iCCA patients, suggesting targeted therapy strategies to enhance the response to chemotherapy [ 22 ].…”