Involvement of PPARy in the antitumoral action of cannabinoids on hepatocellular carcinoma
Autores
Rodríguez Henche, Nieves; Díaz-Laviada Marturet, Inés; Vara Ciruelos, Diana; Morell, María CeciliaIdentificadores
Enlace permanente (URI): http://hdl.handle.net/10017/17301DOI: 10.1038/cddis.2013.141
ISSN: 2041-4889
Editor
Nature Publishing Group
Fecha de publicación
2013Patrocinadores
Ministerio de Economía y Competitividad
Comunidad de Madrid
Universidad de Alcalá
Cita bibliográfica
Cell Death and Disease, 2013, 4, e618
Palabras clave
Cancer Metabolism
Metabolismo del cáncer
Proyectos
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
Tipo de documento
info:eu-repo/semantics/article
Versión
info:eu-repo/semantics/publishedVersion
Versión del editor
http://dx.doi.org/10.1038/cddis.2013.141Derechos
Atribucion-NoComercial-SinDerivadas 3.0 España
© Macmillan Publishers, 2013
Derechos de acceso
info:eu-repo/semantics/openAccess
Resumen
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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