Polyherbal Supplements can Modify Energetics and Lipid Metabolism in Cancer Cells by Activating AMPK Signaling

Abstract

Extensive body of literature demonstrates that a selective blend of herbal extracts inhibit tumor growth at human doses. These tumor suppressive effects are due to multiple mechanisms that arise via synergistic interactions of their components (Huang et al Nutr Ca 2011&2012 and BMC Complement Alternat Med 2014; Zhao et al Func Foods Health Dis 2014). The objective was to determine if the suppressive effects of the polyherbal blend (PHB) involve inhibition of lipogenesis. Cancer cells upregulate lipogenesis via fatty acid synthase (FAS) and acetyl CoA carboxylase (ACC) to generate membrane lipids for rapidly dividing cells. When CWR22Rv1 and PC3 prostate cancer cells were treated with this PHB consisting of 10 well‐defined herbal extracts (see ref above), transcription of FAS and SREBP1c (regulator of FAS) were down regulated and ACC activity was inhibited. AMPK, energy sensor of the cell that regulates multiple steps in lipogenesis, was up regulated by the PHB. RNAi knockdown, pharmacological inhibition/activation, or overexpression of AMPK demonstrated that inhibition of lipogenesis was mediated by the PHB through the activation of AMPK. Inhibition of mTOR signaling (downstream of AMPK) via phosphorylation of raptor and S6K1and down regulation of GβL confirmed involvement of AMPK activation by the PHB. Cellular accumulation of acetyl CoA occurred as a result of inhibition of the lipogenic pathway. The PHB enhanced fatty acid oxidation, an effect likely due to a reduction in malonyl CoA whose levels are regulated by ACC activity. These results suggest that combinations of herbal extracts increase AMPK activation and, in turn, decrease lipogenesis at multiple regulatory sites, in addition to down regulating mTOR signaling and up regulating fatty acid oxidation. (Supported by the TN AES)