First we learned that the cannabinoids produced by the cannabis plant fight and kill cancer cells now we are beginning to uncover the mechanisms by which cannabinoids target and kill cancer cells. Alcohol promotes cancer while marijuana suppresses cancer, what's wrong with this picture? I could go buy gallons and gallons of booze legally, but the government will destroy your life if you market marijuana. Cell Death Dis. 2013 May 2;4:e618. doi: 10.1038/cddis.2013.141.Involvement of PPARγ in the antitumoral action of cannabinoids on hepatocellular carcinoma.Vara D, Morell C, Rodríguez-Henche N, Diaz-Laviada I.SourceBiochemistry and Molecular Biology Unit, Department of System Biology, School of Medicine, University ofAlcala, 28871 Madrid, Spain.AbstractCannabinoids exert antiproliferative effects in a wide range of tumoral cells, including hepatocellular carcinoma HCC cells. In this study, we examined whether the PPARγ-activated pathway contributed to the antitumor effect of two cannabinoids, Δ9-tetrahydrocannabinol THC and JWH-015, against HepG2 and HUH-7 HCC cells. Both cannabinoids increased the activity and intracellular level of PPARγ mRNA and protein, which was abolished by the PPARγ inhibitor GW9662. Moreover, genetic ablation with small interfering RNA siRNA, as well as pharmacological inhibition of PPARγ 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, PPARγ knockdown with siRNA caused accumulation of the autophagy markers LC3-II and p62, suggesting that PPARγ is necessary for the autophagy flux promoted by cannabinoids. Interestingly, downregulation of the endoplasmic reticulum stress-related protein tribbles homolog 3 TRIB3 markedly reduced PPARγ expression and induced p62 accumulation, which was counteracted by overexpression of PPARγ 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 PPARγ-dependent pathways.