Involvement of PPARy in the antitumoral action of cannabinoids on hepatocellular carcinoma

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Title : Involvement of PPARy in the antitumoral action of cannabinoids on hepatocellular carcinoma
Author : Rodríguez-Henche, Nieves; Díaz-Laviada, Inés; Vara Ciruelos, Diana; Morell, Cecilia
Publisher : Nature Publishing Group
Date : 2013
Filiación : Universidad de Alcalá. Departamento de Bioquímica y Biología Molecular
Cita bibliográfica : Cell Death and Disease, 2013, 4, e618
Keyword : Cancer Metabolism
Metabolismo del cáncer
Proyecto : S2010/BMD-2308 (Comunidad de Madrid); EFU2012-31444 (Ministerio de Economía y Competitividad); GC2011-001 (Universidad de Alcalá)
Tipo de documento : info:eu-repo/semantics/article
Enlace permanente (URI) : http://hdl.handle.net/10017/17301
DOI : 10.1038/cddis.2013.141
ISSN : 2041-4889
Versión : info:eu-repo/semantics/publishedVersion
Version of the editor : http://dx.doi.org/10.1038/cddis.2013.141
Derechos : Atribucion-NoComercial-SinDerivadas 3.0 España; © Macmillan Publishers, 2013
Derechos de acceso : info:eu-repo/semantics/openAccess

Abstract :

Cannabinoids exert antiproliferative effects in a wide range of tumoral cells, including hepatocellular carcinoma (HCC) cells. In this study, we examined whether the PPARc-activated pathway contributed to the antitumor effect of two cannabinoids, D9-tetrahydrocannabinol (THC) and JWH-015, against HepG2 and HUH-7 HCC cells. Both cannabinoids increased the activity and intracellular level of PPARc mRNA and protein, which was abolished by the PPARc inhibitor GW9662. Moreover, genetic ablation with small interfering RNA (siRNA), as well as pharmacological inhibition of PPARc decreased the cannabinoid-induced cell death and apoptosis. Likewise, GW9662 totally blocked the antitumoral action of cannabinoids in xenograft-induced HCC tumors in mice. In addition, PPARc knockdown with siRNA caused accumulation of the autophagy markers LC3-II and p62, suggesting that PPARc is necessary for the autophagy flux promoted by cannabinoids. Interestingly, downregulation of the endoplasmic reticulum stress-related protein tribbles homolog 3 (TRIB3) markedly reduced PPARc expression and induced p62 accumulation, which was counteracted by overexpression of PPARc in TRIB3-knocked down cells. Taken together, we demonstrate for the first time that the antiproliferative action of the cannabinoids THC and JWH-015 on HCC, in vitro and in vivo, are modulated by upregulation of PPARc-dependent pathways.


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