title: Apoptosis induced in HepG2 cells by the synthetic cannabinoid WIN: involvement of the transcription factor PPARgamma.
abstract: It has recently been shown that cannabinoids induce growth inhibition and apoptosis in different tumour cell lines. In the current study, the effects of WIN 55,212-2 (WIN), a synthetic and potent cannabinoid receptor agonist, are investigated in hepatoma HepG2 cells and a possible signal transduction pathway is proposed. In these cells, WIN induces a clear apoptotic effect which was accompanied by up-regulation of the death-signalling factors Bax, Bcl-X(S), t-Bid and down-regulation of the survival factors survivin, phospho-AKT, Hsp72 and Bcl-2. Moreover, WIN-induced apoptosis is associated with JNK/p38 MAPK pathway activation and mitochondrial depolarisation demonstrated by a cytofluorimetric assay. The results also show that in HepG2 cells WIN markedly increases the level of the transcription factor PPARgamma in a dose- and time-dependent manner. The addition of the PPARgamma antagonists GW9662 and T0070907 significantly reduces the effects of the drug on both cell viability and the levels of survivin, phospho-AKT and phospho-BAD, suggesting that PPARgamma plays a key role in WIN-induced apoptosis. Altogether, the results seem to indicate a potential therapeutic role of WIN in hepatic cancer treatment.
authors.affiliation: Dipartimento di Scienze Biochimiche, Università di Palermo, Via del Vespro 129, 90127 Palermo, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Giuliano
authors.forename: Ornella
authors.initials: O
authors.lastname: Pellerito
authors.forename: Patrizia
authors.initials: P
authors.lastname: Portanova
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Calvaruso
authors.forename: Andrea
authors.initials: A
authors.lastname: Santulli
authors.forename: Anna
authors.initials: A
authors.lastname: De Blasio
authors.forename: Renza
authors.initials: R
authors.lastname: Vento
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tesoriere
mesh_terms: D000813:Anilides / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology; D048588:Benzoxazines / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D051017:Apoptosis Regulatory Proteins; D001549:Benzamides; D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D047495:PPAR gamma; D011725:Pyridines; D043885:Receptor, Cannabinoid, CB2; C458508:T 0070907; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D011494:Protein Kinases