Involvement of PPARy in the antitumoral action of cannabinoids on hepatocellular carcinoma
Authors
Rodríguez Henche, Nieves; Díaz-Laviada Marturet, Inés; Vara Ciruelos, Diana; Morell, María CeciliaIdentifiers
Permanent link (URI): http://hdl.handle.net/10017/17301DOI: 10.1038/cddis.2013.141
ISSN: 2041-4889
Publisher
Nature Publishing Group
Date
2013Funders
Ministerio de Economía y Competitividad
Comunidad de Madrid
Universidad de Alcalá
Bibliographic citation
Cell Death and Disease, 2013, 4, e618
Keywords
Cancer Metabolism
Metabolismo del cáncer
Project
info:eu-repo/grantAgreement/CAM//S2010%2FBMD-2308/ES/Neurofarmacología del sistema endocannabinoide: del laboratorio a la clínica
info:eu-repo/grantAgreement/MINECO//EFU2012-31444/ES//
info:eu-repo/grantAgreement/UAH//GC2011-001/ES/Efecto de los canabinoides. El metabolismo de células tumorales. Estudio en modelos animales
Document type
info:eu-repo/semantics/article
Version
info:eu-repo/semantics/publishedVersion
Publisher's version
http://dx.doi.org/10.1038/cddis.2013.141Rights
Atribucion-NoComercial-SinDerivadas 3.0 España
© Macmillan Publishers, 2013
Access rights
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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