Glycolysis Inhibition of Autophagy Drives Malignancy in Ovarian Cancer: Exacerbation by IL-6 and Attenuation by Resveratrol

• Published in: International journal of molecular sciences 2023-01, Vol.24 (2), p.1723
• Main Authors: Vidoni, Chiara, Ferraresi, Alessandra, Vallino, Letizia, Salwa, Amreen, Ha, Ji Hee, Seca, Christian, Garavaglia, Beatrice, Dhanasekaran, Danny N, Isidoro, Ciro
• Format: Article
• Language: English
• Subjects: Autophagy; Biochemistry, biophysics & molecular biology; Biochimie, biophysique & biologie moléculaire; Catalysis; Cell adhesion & migration; Cell Line, Tumor; cell migration; Cell proliferation; Computer Science Applications; Cytokines; Female; Fermentation; Functional foods & nutraceuticals; General Medicine; Genomes; Genotype & phenotype; Glucose; Glucose metabolism; Glycolysis; Hexokinase; hexokinase 2; Humans; Inflammation; Inorganic Chemistry; Interleukin 6; Interleukin 6 receptors; Interleukin-6 - metabolism; Lactic acid; Life sciences; Localization; Macromolecules; Malignancy; Medical prognosis; Metabolism; Metabolites; Metastases; Metastasis; Mitochondria; Molecular Biology; Motility; nutraceuticals; Organic Chemistry; Ovarian cancer; Ovarian Neoplasms; Ovarian Neoplasms - metabolism; overall survival; personalized cancer therapy; Phosphorylation; Physical and Theoretical Chemistry; pro-inflammatory cytokines; Pyruvic acid; Reactive oxygen species; Resveratrol; Resveratrol - pharmacology; Resveratrol - therapeutic use; Sciences du vivant; Spectroscopy; TOR protein; Warburg effect; Wound healing
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24021723

Cancer cells drive the glycolytic process towards the fermentation of pyruvate into lactate even in the presence of oxygen and functioning mitochondria, a phenomenon known as the "Warburg effect". Although not energetically efficient, glycolysis allows the cancer cell to synthesize the metabolites needed for cell duplication. Autophagy, a macromolecular degradation process, limits cell mass accumulation and opposes to cell proliferation as well as to cell migration. Cancer cells corrupt cancer-associated fibroblasts to release pro-inflammatory cytokines, which in turn promote glycolysis and support the metastatic dissemination of cancer cells. In mimicking in vitro this condition, we show that IL-6 promotes ovarian cancer cell migration only in the presence of glycolysis. The nutraceutical resveratrol (RV) counteracts glucose uptake and metabolism, reduces the production of reactive oxygen species consequent to excessive glycolysis, rescues the mitochondrial functional activity, and stimulates autophagy. Consistently, the lack of glucose as well as its metabolically inert analogue 2-deoxy-D-glucose (2-DG), which inhibits hexokinase 2 (HK2), trigger autophagy through mTOR inhibition, and prevents IL-6-induced cell migration. Of clinical relevance, bioinformatic analysis of The Cancer Genome Atlas dataset revealed that ovarian cancer patients bearing mutated with low expression of glycolytic markers and IL-6 receptor, together with markers of active autophagy, display a longer overall survival and are more responsive to platinum therapy. Taken together, our findings demonstrate that RV can counteract IL-6-promoted ovarian cancer progression by rescuing glycolysis-mediated inhibition of autophagy and support the view that targeting Warburg metabolism can be an effective strategy to limit the risk for cancer metastasis.