α-Mangostin, a dietary xanthone, induces autophagic cell death by activating the AMP-activated protein kinase pathway in glioblastoma cells

J Agric Food Chem. 2011 Mar 9;59(5):2086-96. doi: 10.1021/jf1042757. Epub 2011 Feb 11.

Abstract

This study is the first to investigate the anticancer effects of α-mangostin in human glioblastoma cells. α-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 α-mangostin-mediated cell death. We also found that liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signaling is a critical mediator of α-mangostin-induced inhibition of cell growth. Activation of AMPK induces α-mangostin-mediated phosphorylation of raptor, which subsequently associates with 14-3-3γ 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 α-mangostin-induced autophagy and raptor phosphorylation, supporting the theory that activation of AMPK is beneficial to autophagy. A further investigation revealed that α-mangostin also induced autophagic cell death in transplanted glioblastoma in nude mice. Together, these results suggest a critical role for AMPK activation in the α-mangostin-induced autophagy of human glioblastoma cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Antineoplastic Agents, Phytogenic / administration & dosage
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Autophagy / drug effects*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Enzyme Activation / drug effects
  • Glioblastoma / pathology*
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Nude
  • Multiprotein Complexes
  • Neoplasm Transplantation
  • Phosphorylation / drug effects
  • Proteins / antagonists & inhibitors
  • Proteins / metabolism
  • Regulatory-Associated Protein of mTOR
  • TOR Serine-Threonine Kinases
  • Xanthones / administration & dosage
  • Xanthones / pharmacology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents, Phytogenic
  • Multiprotein Complexes
  • Proteins
  • RPTOR protein, human
  • Regulatory-Associated Protein of mTOR
  • Xanthones
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • AMP-Activated Protein Kinases
  • mangostin