Antitumoral action of cannabinoids on hepatocellular carcinoma. Role of AMPK-dependent activation of autophagy.

Ines Diaz-Laviada (1) , Diana Vara (1) , Maria Salazar (1) , Nuria Olea-Herrero (1) , Manuel Guzmán (1) , Guillermo Velasco (1)

1 Biochemistry and Molecular Biology

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-tetrahydrocannabinol (Δ-THC, the main active component of Cannabis sativa) and JWH-015 (a CB2 cannabinoid receptor-selective agonist) reduced the viability of the human HCC cell lines HepG2 and HUH-7, an effect that relied on the stimulation of CB2 receptor. We also found that Δ-THC and JWH-015 induced autophagy which relied on TRB3 up-regulation - and subsequent inhibition of the Akt/mTORC1 axis - and AMPK stimulation. Pharmacological and genetic inhibition of AMPK upstream kinases supported that CAMKKβ was responsible for cannabinoid-induced AMPK activation and autophagy. In vivo studies revealed that Δ-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.

Mots clés: Δ-THC; JWH-015; CB2; AMPK; liver

Ines Diaz-Laviada, Diana Vara, Maria Salazar, Nuria Olea-Herrero, Manuel Guzmán, et al.. Antitumoral action of cannabinoids on hepatocellular carcinoma. Role of AMPK-dependent activation of autophagy.. Cell Death and Differentiation, 2011, ⟨10.1038/cdd.2011.32⟩. ⟨hal-00630276⟩