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Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy.
Cell Death Differ. 2011 Jul; 18(7):1099-111.CD

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.

Authors+Show Affiliations

Department of Biochemistry and Molecular Biology, School of Medicine, Alcalá University, Madrid, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21475304

Citation

Vara, D, et al. "Anti-tumoral Action of Cannabinoids On Hepatocellular Carcinoma: Role of AMPK-dependent Activation of Autophagy." Cell Death and Differentiation, vol. 18, no. 7, 2011, pp. 1099-111.
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. 2011;18(7):1099-111.
Vara, D., Salazar, M., Olea-Herrero, N., Guzmán, M., Velasco, G., & Díaz-Laviada, I. (2011). Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy. Cell Death and Differentiation, 18(7), 1099-111. https://doi.org/10.1038/cdd.2011.32
Vara D, et al. Anti-tumoral Action of Cannabinoids On Hepatocellular Carcinoma: Role of AMPK-dependent Activation of Autophagy. Cell Death Differ. 2011;18(7):1099-111. PubMed PMID: 21475304.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy. AU - Vara,D, AU - Salazar,M, AU - Olea-Herrero,N, AU - Guzmán,M, AU - Velasco,G, AU - Díaz-Laviada,I, Y1 - 2011/04/08/ PY - 2011/4/9/entrez PY - 2011/4/9/pubmed PY - 2011/10/1/medline SP - 1099 EP - 111 JF - Cell death and differentiation JO - Cell Death Differ VL - 18 IS - 7 N2 - 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. SN - 1476-5403 UR - https://www.unboundmedicine.com/medline/citation/21475304/Anti_tumoral_action_of_cannabinoids_on_hepatocellular_carcinoma:_role_of_AMPK_dependent_activation_of_autophagy_ L2 - https://doi.org/10.1038/cdd.2011.32 DB - PRIME DP - Unbound Medicine ER -