RT Journal Article
T1 Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy
A1 Vara, Diana
A1 Olea-Herrero, Nuria
A1 Salazar Roa, María
A1 Guzmán Pastor, Manuel
A1 Velasco Díez, Guillermo
A1 Díaz-Laviada Marturet, Inés
AB 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 Δ9-tetrahydrocannabinol (Δ9-THC, the main active component of Cannabis sativa) and JWH-015 (a cannabinoid receptor 2 (CB2) 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 CB2 receptor. We also found that Δ9-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 Δ9-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.
PB Springer
SN 1350-9047
YR 2011
FD 2011
LK https://hdl.handle.net/20.500.14352/97853
UL https://hdl.handle.net/20.500.14352/97853
LA eng
NO Vara, D., Salazar, M., Olea-Herrero, N. et al. Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy. Cell Death Differ 18, 1099–1111 (2011). https://doi.org/10.1038/cdd.2011.32
NO AcknowledgementsThis work was supported by Ministerio de Ciencia e Innovación (Grant SAF2008-03220 to ID, PS09/01401 to GV and SAF2006/00918 to MG), Comunidad de Madrid (Grants CAM/UAH CCG08-UAH/BIO-3914 and CAM S-SAL-0261-2006), Comunidad Castilla-LaMancha (Grant PII1/09-0165-0822) and Santander-Complutense (Grant PR34/07-15856 to GV). NO-H and DV received fellowships from the University of Alcalá. MS was recipient of a fellowship from MEC and of a formation contract from Comunidad de Madrid. We thank Sonia Hernández, Mar Lorente and Sofía Torres for their technical advice as well as other members of our laboratories for their continuous support.
NO Ministerio de Ciencia e Innovación (España)
NO Comunidad de Madrid
NO Junta de Comunidades de Castilla-LaMancha
NO Universidad de Alcalá
NO Universidad Complutense de Madrid
DS Docta Complutense
RD 23 ene 2026