Targeting Glycolysis-Dependent Inhibition of Autophagy Reduces Ovarian Cancer Cell Migration and Impairs CAF Phenoconversion

Introduction Cancer cells exploit aerobic glycolysis, also known as the Warburg effect, which consists of the fermentation of pyruvate into lactate, even in the presence of oxygen and functioning mitochondria. This metabolic rewiring fuels the uncontrolled growth of the tumor mass and promotes cancer progression. Glycolytic reprogramming occurs not exclusively in cancer cells but also in the stroma, especially in cancer-associated fibroblasts (CAFs), a process that has been named the “reverse Warburg effect”. Autophagy, an evolutionary conserved catabolic process devoted to macromolecular turnover, is often dysregulated in cancer and plays a "double-edged sword" role in regulating the tumor microenvironment.

Methods To mimic the tumor microenvironment in vitro, we employed IL-6, a pro-inflammatory cytokine abundant in ovarian cancer patients, and we set up an indirect co-culture method by cultivating fibroblasts with the conditioning medium of ovarian cancer cells.

Results Our work aimed to dissect how the glycolysis/autophagy interplay affects ovarian cancer cell motility and the phenoconversion of CAFs. Our data show that IL-6 induces cancer cell migration only in cases of active glycolysis. On the other hand, nutraceutical resveratrol (RV) inhibits glucose uptake and metabolism while promoting autophagy, collectively hampering cancer cell motility. Moreover, our bioinformatic interrogation of TCGA data shows that patients with a low expression of glycolytic markers and displaying active autophagy exhibit favorable clinical outcomes. Next, we show that the glycolysis-dependent inhibition of autophagy promotes CAF activation. The conditioning medium of the ovarian cancer cells induces the glycolytic reprogramming that is required for CAF activation. Notably, glycolysis inhibition using 2-deoxy-D-glucose (2DG) or RV induces autophagy, which reprograms the CAFs into quiescent fibroblasts.

Conclusions Taken together, our data support the use of glycolysis inhibitors and/or autophagy inducers as an adjuvant strategy to improve the therapy success rate and limit the risk of metastasis.