Targeting tumor glycolysis metabolism in oral squamous cell carcinoma cells by brusatol

Abstract

Brusatol is a natural quassinoid terpenoid that shows a potential therapeutic use in treating various ailments. Recently, brusatol was shown to have anti-tumor activity and ameliorating chemoresistance or enhancing chemotherapeutic drug efficacy in vitro and in vivo cancer models, but its molecular mechanisms remained to be clarified. Here, we aim to investigate the roles of brusatol in oral squamous cell carcinoma (OSCC) cells and its possible mechanism, especially on tumor cell glycolytic metabolism. In this study, we found that brusatol exerted significant anti-tumor effects in OSCC cells by repressing tumor cells proliferation, cycles, migration, invasion, and colony formation and inducing cell apoptosis in vitro through MTT, cell cycle, cell migration and invasion, colony formation and cell apoptosis assays. The result of metabolic assay and Seahorse XF glycolysis stress test assay showed that brusatol directly targeted glycolysis by inhibiting the extracellular acidification rate represented by a decreased glycolysis, glycolytic capacity and reserve capacity, and repressing activity of the key glycolytic enzymes pyruvate kinase and hexokinase. We also found that the expression of glucose transporter 1 (GLUT1) and several important glycolysis related genes, including HIF-1α and c-Myc was downregulated by brusatol through real-time PCR. Furthermore, in vivo studies supported anti-tumor role for brusatol, demonstrating that brusatol inhibited tumor growth, angiogenesis, glycolysis metabolism and induction of apoptosis in OSCC cells nude mice xenografts. Our data clearly demonstrated the anti-tumor effects of brusatol in OSCC cells by targeting glycolytic metabolism, and it could become a promising tumor chemotherapeutic agent in oral cancer.

Keywords

• Brusatol
• Glycolytic metabolism
• Oral squamous cell carcinoma
• Apoptosis