Resveratrol Attenuates the Malignant Phenotype of Ovarian Cancer Cells via Epigenetic Regulation of Autophagy

Ovarian cancer emerges as a highly aggressive metastatic disease characterized by a high grade of lethality due to its asymptomatic nature and the late diagnosis. Autophagy, a lysosomal-driven catabolic process that ensures intracellular homeostasis, is dysregulated in ovarian cancer. We found that the migratory promoting effect of IL-6, a pro-inflammatory cytokine released by tumor microenvironment, was dependent on inhibition of autophagy. Resveratrol (RV), a natural occurring polyphenol, counteracts this effect by epigenetically restoring autophagy in the cells at the migration front. Interestingly, IL-6 and RV modulated in an opposite fashion the expression of ARH-I, an oncosuppressor protein that interacts with BECLIN-1. Spautin-1, by inducing proteasome degradation of BECLIN-1, abrogates RV benefits and promotes cell migration, indicating that BECLIN-1-dependent autophagy is crucial in preventing tumor invasion. Another open issue that limit the survival of ovarian cancer patient is the low efficacy of therapies due to development of chemoresistance and relapse. We found that both RV and starvation trigger Amino Acid Response (AAR) and autophagy, even if this latter through different pathways. Yet, the AAR was greater in starved cells, while autophagy was prominent in RV-treated cells. Indeed, the number of transcripts positively impinging on autophagy pathway was higher in RV-treated than in starved cancer cells. Also, RV still permitted some protein synthesis while starvation completely blocked the process of protein translation. Our data support the view that Resveratrol can be more effective than and could substitute starvation as an adjuvant strategy to sensitize cancer cells to chemotherapy. Taken together, our findings highlight that targeting the pathways through which autophagy regulates tumorigenic features of cancer cells could represent a novel and more effective anti cancer therapy and may provide long-term benefits to ovarian cancer patients.