Resveratrol Targets Glycolytic Enzymes HK II and PKM2 to Promote Concurrent Apoptotic and Necrotic Cell Death in Malignant Melanoma

Malignant melanoma exhibits high metastatic potential and resistance to chemotherapy, highlighting the need for novel therapeutic strategies. Resveratrol, a natural polyphenol, exerts anticancer effects by modulating cellular metabolism and apoptosis. In this study, we investigated its effects on hexokinase II (HK II) and pyruvate kinase M2 (PKM2) in G361 and SK-MEL-24 melanoma cells. Resveratrol reduced HK II and PKM2 expression and enzymatic activity, resulting in decreased ATP production and inhibition of glycolysis-dependent energy metabolism. Apoptosis was induced, as indicated by increased cleaved caspase-3, elevated Bax/Bcl-2 ratio, and enhanced caspase-3/7 activity. Necroptosis was also activated, evidenced by increased phosphorylation of RIP and MLKL. Cell cycle analysis revealed G0/G1 phase arrest, and Annexin V staining confirmed apoptosis. These effects were stronger in G361 cells than in SK-MEL-24 cells, suggesting that HK II- and PKM2-dependent metabolic traits influence resveratrol sensitivity. In summary, resveratrol activates both apoptotic and necroptotic cell-death pathways by inhibiting HK II and PKM2, highlighting its potential as a metabolism-targeted therapeutic agent for malignant melanoma.