Involvement of PAR-4 in cannabinoid-dependent sensitization of osteosarcoma cells to TRAIL-induced apoptosis.
The synthetic cannabinoid WIN 55,212-2 is a potent cannabinoid receptor agonist with anticancer potential. Experiments were performed to determine the effects of WIN on proliferation, cell cycle distribution, and programmed cell death in human osteosarcoma MG63 and Saos-2 cells. Results show that WIN induced G2/M cell cycle arrest, which was associated with the induction of the main markers of ER stress (GRP78, CHOP and TRB3). In treated cells we also observed the conversion of the cytosolic form of the autophagosome marker LC3-I into LC3-II (the lipidated form located on the autophagosome membrane) and the enhanced incorporation of monodansylcadaverine and acridine orange, two markers of the autophagic compartments such as autolysosomes. WIN also induced morphological effects in MG63 cells consisting in an increase in cell size and a marked cytoplasmic vacuolization. However, WIN effects were not associated with a canonical apoptotic pathway, as demonstrated by the absence of specific features, and only the addition of TRAIL to WIN-treated cells led to apoptotic death probably mediated by up-regulation of the tumor suppressor factor PAR-4, whose levels increased after WIN treatment, and by the translocation of GRP78 on cell surface.
['Notaro|Antonietta|A|', 'Sabella|Selenia|S|', 'Pellerito|Ornella|O|', 'Di Fiore|Riccardo|R|', 'De Blasio|Anna|A|', 'Vento|Renza|R|', 'Calvaruso|Giuseppe|G|', 'Giuliano|Michela|M|']
D000165:Acridine Orange D017209:Apoptosis D051017:Apoptosis Regulatory Proteins D048588:Benzoxazines D002103:Cadaverine D063386:Cannabinoid Receptor Agonists D059447:Cell Cycle Checkpoints D045744:Cell Line, Tumor D049109:Cell Proliferation D000091342:Endoplasmic Reticulum Chaperone BiP D059865:Endoplasmic Reticulum Stress D006360:Heat-Shock Proteins D006801:Humans D008869:Microtubule-Associated Proteins D009025:Morpholines D009281:Naphthalenes D012516:Osteosarcoma D034741:RNA, Small Interfering D053221:TNF-Related Apoptosis-Inducing Ligand
osteosarcoma cells Cannabinoids ER stress TRAIL GRP78/PAR-4 complex. autophagy