Abstract
Cannabinoids 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.
Highlights
Cannabinoids are bioactive lipids that have been shown to modulate many physiological and pathological conditions
It has been demonstrated that the synthetic cannabinoid WIN 55,212-2 (WIN) induces apoptosis in the Hepatocellular carcinoma (HCC) HepG2 cell line, which is associated with an increase in PPARg expression.[18]
We have previously described that the cannabinoids D9-tetrahydrocannabinol (THC), the main psychoactive component of the Cannabis sativa plant, and JWH-015, a synthetic selective ligand of CB2, exert antiproliferative effects and induce autophagy on the HCC cell lines HepG2 and HuH-7.19 As cannabinoids have well-known palliative effects on some cancer-associated and
Summary
Cannabinoids are bioactive lipids that have been shown to modulate many physiological and pathological conditions. It has been previously described that cannabinoids arrest cell proliferation, reduce cell migration and inhibit angiogenesis, and cannabinoid-like compounds offer a therapeutic potential for the treatment of many types of cancer.[3,4,5] the well-defined cannabinoid receptors are the GPCR receptor types CB1 and CB2, cannabinoids may impact other putative targets such as nuclear receptors PPARs.[6,7] PPARs are ligand-activated transcription factors, which belong to the nuclear receptor superfamily and mediate several physiological functions, among which the best characterized are lipid metabolism, energy balance and antiinflammation.[8] There are three PPAR subtypes: alpha, delta ( known as beta) and gamma, all of which have long been known to be expressed in the liver, at different levels.[9] PPARg exists in two major isoforms (g1 and g2) that arise by differential transcription start sites and alternative splicing,[10] albeit PPARg1 expression is very low in most tissues including the liver. We investigated whether PPARg is involved in the antiproliferative effect of cannabinoids on HCC cells and its relationship with the previously identified signalling pathways
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