Apoptosis induced in HepG2 cells by the synthetic cannabinoid WIN: involvement of the transcription factor PPARgamma.
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.
Giuliano
Michela
M
Dipartimento di Scienze Biochimiche, Università di Palermo, Via del Vespro 129, 90127 Palermo, Italy.
Pellerito
Ornella
O
Portanova
Patrizia
P
Calvaruso
Giuseppe
G
Santulli
Andrea
A
De Blasio
Anna
A
Vento
Renza
R
Tesoriere
Giovanni
G
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
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