The metabolic setting of ovarian cancer cells modifies response to chemotherapy

Ovarian cancer (OC) conventional treatment includes cytoreductive surgery followed by taxane- and platinum-based chemotherapy. However, despite initial response, 85% of treated patients develops chemoresistance and often relapses. Therefore, the understanding of the still elusive mechanisms leading to therapeutic resistance is a major challenge for the development of more effective treatments. Metabolic reprogramming has emerged as crucial for tumour progression with growing evidence showing that OC cells switch their metabolism between aerobic glycolysis and oxidative phosphorylation (OXPHOS) to sustain tumour proliferation, invasiveness, and chemoresistance. However, which metabolism is preferred by chemoresistant cells is highly debated. Our analyses revealed that metabolically energetic chemo-naïve OC cell lines, using both glycolysis and OXPHOS, were more responsive to platinum-based treatment, whereas purely glycolytic cells were chemoresistant. We found higher abundance and activity of mitochondrial respiratory complexes in chemosensitive OC cell lines. High-OXPHOS status correlated with the expression of PGC-1 family of transcriptional co-activators and depended mainly on pyruvate-mediated TCA cycle fuelling. In hypoxia, we observed an increase in chemoresistance that was prevented by HIF1α ablation. Importantly, the acquisition of cisplatin-resistance in two energetic cell lines induced a shift to a quiescent metabolism with reduction of both glycolytic and OXPHOS function when compared to their syngeneic sensitive counterparts. Overall, our findings suggest that a high-OXPHOS condition is associated with chemosensitivity and upregulation of such metabolism may be a possible therapeutic strategy to overcome chemoresistance