Cryptotanshinone suppresses ovarian cancer via simultaneous inhibition of glycolysis and oxidative phosphorylation

Abstract

Ovarian cancer is one of the most lethal cancers in female reproductive system due to heterogeneity and lack of effective treatment. Targeting aerobic glycolysis, a predominant energy metabolism of cancer cells has been recognized a novel strategy to overcome cancer cell growth. However, the capability of cancer cells to undergo metabolic reprogramming guarantees their survival even when glycolysis is inhibited. Here in this study, we have shown that Cryptotanshinone (CT), a lipid-soluble bioactive anticancer molecule of Salvia miltiorrhiza, inhibits both glycolysis and oxidative phosphorylation (OXPHOS) in ovarian cancer cells leading to growth suppression and apoptosis induction. Our mechanistic study revealed that CT decreased glucose uptake and lactate production, and inhibited the kinase activity of LDHA and HK2. The molecular docking study showed that CT could directly bind with GLUT1, LDHA, HK2, PKM2 and complex-1. The immunoblotting data showed that CT decreased the expression of aberrantly activated glycolytic proteins includingGLUT1, LDHA, HK2, and PKM2. Besides, we found that CT inhibited mitochondrial ComplexⅠ activity, decreased the ratio of NAD+/NADH, and suppressed the generation of ATP and induced activation of AMPK, which controls energy-reducing processes. These in vitro findings were further validated using xenograft model. The findings of in vivo studies were in line with in vitro studies. Taken together, CT effectively suppressed glycolysis and OXPHOS, inhibited growth and induced apoptosis in ovarian cancer cells both in vitro and in vivo study models.