Apoptosis induced in HepG2 cells by the synthetic cannabinoid WIN: involvement of the transcription factor PPARgamma

• Published in: Biochimie Vol. 91; no. 4; pp. 457 - 465
• Main Authors: Giuliano, Michela, Pellerito, Ornella, Portanova, Patrizia, Calvaruso, Giuseppe, Santulli, Andrea, De Blasio, Anna, Vento, Renza, Tesoriere, Giovanni
• Format: Journal Article
• Language: English
• Published: France 01.04.2009
• Subjects: Anilides - pharmacology; Apoptosis; Apoptosis Regulatory Proteins - drug effects; Apoptosis Regulatory Proteins - metabolism; Benzamides - pharmacology; Benzoxazines - pharmacology; Cannabinoids - pharmacology; Carcinoma, Hepatocellular - metabolism; Cell Line, Tumor; Cell Survival - drug effects; Humans; Liver Neoplasms - metabolism; Membrane Microdomains - drug effects; Membrane Microdomains - metabolism; Morpholines - pharmacology; Naphthalenes - pharmacology; PPAR gamma - agonists; PPAR gamma - antagonists & inhibitors; PPAR gamma - metabolism; Protein Kinases - drug effects; Protein Kinases - metabolism; Pyridines - pharmacology; Receptor, Cannabinoid, CB2 - agonists; Receptor, Cannabinoid, CB2 - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology
• ISSN: 1638-6183
• DOI: 10.1016/j.biochi.2008.11.003

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.