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Cell Cycle, Cell Death, and Senescence

Protease-Activated Receptor-1 (hPar1), A Survival Factor Eliciting Tumor Progression

Department of Oncology, Hadassah-Hebrew University Hospital, Jerusalem, Israel

Requests for reprints: Rachel Bar-Shavit, Department of Oncology, Hadassah-Hebrew University Hospital, P.O. Box 12000, Jerusalem 91120, Israel. Phone: 972-2-6777563; Fax: 972-2-6422794. E-mail: barshav{at}md.huji.ac.il

Although ample evidence point to the central involvement of protease activated receptor-1 (PAR1) in tumor progression, little is known about the fate of the tumor when hPar1 is being silenced. We observed that hPar1 antisense clones exhibit low PAR1 levels, attenuated cell proliferation and invasion in vitro, and tumor formation in vivo. These clones showed noticeably reduced paxillin phosphorylation compared with the parental A375SM cells, whereas no change in the integrin levels was noticed. Antisense clones injected into the mice resulted in very few and only occasional small tumors, whereas advanced and vascularized tumors were observed in A375SM cells. The antisense-derived tumor sections expressed active caspase-3, increased terminal deoxynucleotidyl transferase–mediated nick-end labeling staining, and a markedly reduced proliferating cell nuclear antigen level compared with A375SM cell–derived tissue sections. Likewise, ablation of the hPar1 gene in a tetracycline-inducible hPar1 system leads to apoptosis in immature blood vessels, whereas mature vessels were unaffected. The activation of PAR1-induced pAkt/protein kinase B abrogated serum-deprived Bim_EL induction and also markedly inhibited Bax levels. On the other hand, small interfering RNA silencing of the hPar1 gene induced the expression of Bim_EL, a direct substrate of Akt/protein kinase B and also induced expression of active caspase-9 and caspase-3. These results altogether identify PAR1 as a survival factor that protects cells from undergoing apoptosis. We conclude that whereas PAR1 gene expression correlates with tumor progression, its neutralization effectively initiates an apoptotic pathway leading at least in part to significantly reduced tumor formation. (Mol Cancer Res 2007;5(3):229–40)