Oleanolic acid induces metabolic adaptation in cancer cells by activating the AMP-activated protein kinase pathway

Cancer cells are well-known to require a constant supply of protein, lipid, RNA, and DNA via altered metabolism for accelerated cell proliferation. Targeting metabolic pathways is, therefore, a promising therapeutic strategy for cancers. Oleanolic acid (OA) is widely distributed in dietary and medicinal plants and displays a selective cytotoxicity to cancer cells, primarily by inducing apoptosis and cell cycle arrest. This study investigated if OA inhibited growth of tumor cells by affecting their metabolism. OA was found to activate AMP-activated protein kinase (AMPK), the master regulator of metabolism, in prostate cancer cell line PC-3 and breast cancer cell line MCF-7. AMPK activation is required for the antitumor activity of OA on cancer cells. Lipogenesis, protein synthesis, and aerobic glycolysis were inhibited in cancer cells treated with OA, in an AMPK activation-dependent manner. The metabolic alteration was shown to mediate the tumor suppressor activity of OA on cancer cells. Collectively, this study provides evidence that OA, as a widely distributed nutritional component, is able to exert antitumor function by interfering in the metabolic pathway in cancer cells. This finding should encourage researchers to study if affecting cancer metabolism is a common mechanism by which nutritional compounds suppress cancers.