α-Mangostin, a Dietary Xanthone, Induces Autophagic Cell Death by Activating the AMP-Activated Protein Kinase Pathway in Glioblastoma Cells

This study is the first to investigate the anticancer effects of alpha-mangostin in human glioblastoma cells. alpha-Mangostin decreases cell viability by inducing autophagic cell death but not apoptosis. Pretreatment of cells with the autophagy inhibitors 3-methyladenine (3-MA) and bafilomycin or knockdown beclin-1, resulted in the suppression of alpha-mangostin-mediated cell death. We also found that liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signaling is a critical mediator of alpha-mangostin-induced inhibition of cell growth. Activation of AMPK induces alpha-mangostin-mediated phosphorylation of raptor, which subsequently associates with 14-3-3 gamma and results in the loss of mTORC1 activity. The phosphorylation of both downstream targets of mTORC1, p70 ribosomal protein S6 kinase (p70S6 kinase) and 4E-BP1, is also diminished by activation of AMPK. Furthermore, the inhibition of AMPK expression with shRNAs or an inhibitor of AMPK reduced alpha-mangostin-induced autophagy and raptor phosphorylation, supporting the theory that activation of AMPK is beneficial to autophagy. A further investigation revealed that alpha-mangostin also induced autophagic cell death in transplanted glioblastoma in nude mice. Together, these results suggest a critical role for AMPK activation in the alpha-mangostin-induced autophagy of human glioblastoma cells.