title: The secreted protein acidic and rich in cysteine is a critical mediator of cell death program induced by WIN/TRAIL combined treatment in osteosarcoma cells.
abstract: Secreted protein acidic and rich in cysteine (SPARC) is a multi-functional protein which modulates cell-cell and cell-matrix interactions. In cancer cells, SPARC behaves as a tumor promoter in a number of tumors, but it can also act as a tumor suppressor factor. Our previous results showed that the synthetic cannabinoid WIN55,212-2 (WIN), a potent cannabinoid receptor agonist, is able to sensitize osteosarcoma MG63 cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis which is accompanied with endoplasmic reticulum (ER)-stress induction and the increase in autophagic markers. In the present investigation, we studied the role of SPARC in WIN/TRAIL-induced apoptosis demonstrating that WIN increased the level of SPARC protein and mRNA in a time-dependent manner. This event was functional to WIN/TRAIL-dependent apoptosis as demonstrated by RNA interfering analysis which indicated that SPARC-silenced cells were less sensitive to cytotoxic effects induced by the combined treatment. Our experiments also demonstrate that SPARC interacts with caspase-8 thus probably favoring its translocation to plasma membrane and the activation of extrinsic apoptotic pathway. In conclusion, to the best of our knowledge, our results are the first to show that WIN-dependent increase in the level of SPARC plays a critical role in sensitizing osteosarcoma cells to TRAIL action.
authors.affiliation: Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Laboratory of Biochemistry, University of Palermo, Polyclinic, Palermo 90128, Italy.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Notaro
authors.affiliation: Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Laboratory of Biochemistry, University of Palermo, Polyclinic, Palermo 90128, Italy.
authors.forename: Selenia
authors.initials: S
authors.lastname: Sabella
authors.affiliation: Department of Genetics and Development, Toronto Western Hospital, Toronto, ON M5T 2S8, Canada.
authors.forename: Ornella
authors.initials: O
authors.lastname: Pellerito
authors.affiliation: Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Laboratory of Biochemistry, University of Palermo, Polyclinic, Palermo 90128, Italy.
authors.forename: Renza
authors.initials: R
authors.lastname: Vento
authors.affiliation: Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Laboratory of Biochemistry, University of Palermo, Polyclinic, Palermo 90128, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Calvaruso
authors.affiliation: Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Laboratory of Biochemistry, University of Palermo, Polyclinic, Palermo 90128, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Giuliano
mesh_terms: D017209:Apoptosis; D048588:Benzoxazines / Q000737:chemistry; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology; D053181:Caspase 8 / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D059865:Endoplasmic Reticulum Stress; D020868:Gene Silencing; D006801:Humans; D009025:Morpholines / Q000737:chemistry; D009281:Naphthalenes / Q000737:chemistry; D015676:Osteonectin / Q000378:metabolism*; D012516:Osteosarcoma / Q000378:metabolism* / Q000473:pathology; D000072417:Protein Domains; D034622:RNA Interference; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*
chemical_list: D048588:Benzoxazines; D009025:Morpholines; D009281:Naphthalenes; D015676:Osteonectin; C577241:SPARC protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C505530:CASP8 protein, human; D053181:Caspase 8