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.
Highlights
Ovarian cancer (OC) encompasses a heterogenous group of malignancies differentiated by cell/site of origin, pathological grade, risk factors, prognosis, and treatment
We have previously demonstrated that the expression of the molecular chaperone Tumor necrosis factor Receptor Associated Protein 1 (TRAP1) in HGSOC inversely correlates with stage, grade, and progression to metastatic disease and directly correlates with survival [7,9]
HGSOC is responsible for the majority of deaths and, even though the the introduction of PARP inhibitors led to large advances, improvements are still needed for a more introduction of PARP inhibitors led to large advances, improvements are still needed for a more successful therapy
Summary
Ovarian cancer (OC) encompasses a heterogenous group of malignancies differentiated by cell/site of origin, pathological grade, risk factors, prognosis, and treatment. Among all OC subtypes, non-epithelial neoplasias are the least aggressive, whereas epithelial malignancies are the most common ones, accounting for 90% of all cases [1]. Epithelial cancers (EOC) are classified by tumor cell histology as serous (52%), endometrioid (10%), mucinous (6%), or clear cell (6%), with the rest being rarer subtypes or unspecified [1]. Cells 2020, 9, 828 clinicopathologic factors, with type I classified as low-grade malignancies, except clear cell carcinomas, and accounting for only a small fraction of deaths, and type II considered high grade tumors and characterized by aggressiveness and low survival [2]. The predominant high-grade serous carcinomas are mostly diagnosed at stage III (51%) or IV (29%), reflecting their poorly symptomatic and aggressive nature. The five-year cause-specific survival for serous carcinoma is 43%, compared with
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