Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy

Cell Death Differ. 2011 Jul;18(7):1099-111. doi: 10.1038/cdd.2011.32. Epub 2011 Apr 8.

Abstract

Hepatocellular carcinoma (HCC) is the third cause of cancer-related death worldwide. When these tumors are in advanced stages, few therapeutic options are available. Therefore, it is essential to search for new treatments to fight this disease. In this study, we investigated the effects of cannabinoids--a novel family of potential anticancer agents--on the growth of HCC. We found that Δ(9)-tetrahydrocannabinol (Δ(9)-THC, the main active component of Cannabis sativa) and JWH-015 (a cannabinoid receptor 2 (CB(2)) cannabinoid receptor-selective agonist) reduced the viability of the human HCC cell lines HepG2 (human hepatocellular liver carcinoma cell line) and HuH-7 (hepatocellular carcinoma cells), an effect that relied on the stimulation of CB(2) receptor. We also found that Δ(9)-THC- and JWH-015-induced autophagy relies on tribbles homolog 3 (TRB3) upregulation, and subsequent inhibition of the serine-threonine kinase Akt/mammalian target of rapamycin C1 axis and adenosine monophosphate-activated kinase (AMPK) stimulation. Pharmacological and genetic inhibition of AMPK upstream kinases supported that calmodulin-activated kinase kinase β was responsible for cannabinoid-induced AMPK activation and autophagy. In vivo studies revealed that Δ(9)-THC and JWH-015 reduced the growth of HCC subcutaneous xenografts, an effect that was not evident when autophagy was genetically of pharmacologically inhibited in those tumors. Moreover, cannabinoids were also able to inhibit tumor growth and ascites in an orthotopic model of HCC xenograft. Our findings may contribute to the design of new therapeutic strategies for the management of HCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Autophagy / drug effects
  • Carcinoma, Hepatocellular / drug therapy*
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Dronabinol / therapeutic use*
  • Humans
  • Indoles / therapeutic use*
  • Liver Neoplasms / drug therapy*
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Nude
  • Multiprotein Complexes
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, Cannabinoid, CB2 / agonists
  • Receptor, Cannabinoid, CB2 / metabolism
  • Repressor Proteins / metabolism
  • TOR Serine-Threonine Kinases
  • Transplantation, Heterologous

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Indoles
  • Multiprotein Complexes
  • Proteins
  • Receptor, Cannabinoid, CB2
  • Repressor Proteins
  • TRIB3 protein, human
  • Dronabinol
  • Protein Kinases
  • AMP-activated protein kinase kinase
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • JHW 015