Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells

J Clin Invest. 2009 May;119(5):1359-72. doi: 10.1172/jci37948.

Abstract

Autophagy can promote cell survival or cell death, but the molecular basis underlying its dual role in cancer remains obscure. Here we demonstrate that delta(9)-tetrahydrocannabinol (THC), the main active component of marijuana, induces human glioma cell death through stimulation of autophagy. Our data indicate that THC induced ceramide accumulation and eukaryotic translation initiation factor 2alpha (eIF2alpha) phosphorylation and thereby activated an ER stress response that promoted autophagy via tribbles homolog 3-dependent (TRB3-dependent) inhibition of the Akt/mammalian target of rapamycin complex 1 (mTORC1) axis. We also showed that autophagy is upstream of apoptosis in cannabinoid-induced human and mouse cancer cell death and that activation of this pathway was necessary for the antitumor action of cannabinoids in vivo. These findings describe a mechanism by which THC can promote the autophagic death of human and mouse cancer cells and provide evidence that cannabinoid administration may be an effective therapeutic strategy for targeting human cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Chloromethyl Ketones / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Autophagy / drug effects*
  • Autophagy / physiology
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cannabinoids / pharmacology*
  • Cannabinoids / therapeutic use
  • Caspase 3 / metabolism
  • Cell Cycle Proteins / metabolism
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Dronabinol / pharmacology
  • Dronabinol / therapeutic use
  • Endoplasmic Reticulum / drug effects*
  • Endoplasmic Reticulum / pathology
  • Enzyme Inhibitors / pharmacology
  • Eukaryotic Initiation Factor-2 / metabolism
  • Glioma / drug therapy
  • Glioma / metabolism
  • Glioma / pathology*
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Microtubule-Associated Proteins / metabolism
  • Models, Biological
  • Multiprotein Complexes
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteins
  • Proto-Oncogene Proteins c-akt / metabolism
  • Repressor Proteins / metabolism
  • Ribosomal Protein S6 Kinases / metabolism
  • TOR Serine-Threonine Kinases
  • Transcription Factors / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Amino Acid Chloromethyl Ketones
  • Basic Helix-Loop-Helix Transcription Factors
  • Cannabinoids
  • Cell Cycle Proteins
  • Enzyme Inhibitors
  • Eukaryotic Initiation Factor-2
  • Microtubule-Associated Proteins
  • Multiprotein Complexes
  • Neoplasm Proteins
  • P8 protein, human
  • Proteins
  • Repressor Proteins
  • TRIB3 protein, human
  • Transcription Factors
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • light chain 3, human
  • Dronabinol
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases
  • Caspase 3