Protease‐activated receptor‐1 impedes prostate and intestinal tumor progression in mice. (27th September 2018)

• Record Type: Journal Article
• Authors: Adams, G. N.; Sharma, B. K.; Rosenfeldt, L.; Frederick, M.; Flick, M. J.; Witte, D. P.; Mosnier, L. O.; Harmel‐Laws, E.; Steinbrecher, K. A.; Palumbo, J. S.
• Is Part Of: Journal of thrombosis and haemostasis. Volume 16:Number 11(2018)
• Page Start: 2258
• Page End: 2269
• Publication Date: 2018-09-27
• Subjects: apoptosis -- blood coagulation -- colonic neoplasms -- prostatic neoplasms -- protease‐activated -- receptors; Thrombosis -- Periodicals; Hemostasis -- Periodicals; Blood coagulation disorders -- Periodicals; 616.1
• DOI: 10.1111/jth.14277
• Languages: English
• ISSNs: 1538-7933

Abstract

Abstract : Essentials Protease activated receptor‐1 (PAR‐1) has been proposed to drive cancer progression. Surprisingly, PAR‐1 deletion accelerated tumor progression in two distinct experimental settings. PAR‐1 deletion was shown to limit the apoptosis of transformed epithelial cells. Thrombin‐ and activated protein C‐mediated PAR‐1 activation have unique effects on tumor cell biology. Summary: Background: Multiple studies have implicated protease‐activated receptor‐1 (PAR‐1), a G‐protein‐coupled receptor activated by proteolytic cleavage of its N‐terminus, as one target coupling thrombin‐mediated proteolysis to tumor progression. Objective: To analyze the role of PAR‐1 in the setting of two distinct spontaneously developing tumor models in mice. Methods: We interbred PAR‐1‐deficient mice with Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice, which spontaneously develop prostate tumors, and adenomatous polyposis coli Min (APC M in/+ ) mice, which spontaneously develop intestinal adenomas. Results: Analyses of TRAMP mice with advanced disease (30 weeks) revealed that PAR‐1 deficiency resulted in significantly larger and more aggressive prostate tumors. Prostates collected at an earlier time point (12 weeks of age) revealed that PAR‐1 promotes apoptosis in transformed epithelia. In vitro analyses of TRAMP‐derived cells revealed that activated protein C‐mediated PAR‐1 cleavage can induce tumor cell apoptosis, suggesting that tumor cell‐intrinsic PAR‐1 functions can limit tumor progression. Paralleling results in TRAMP mice, PAR‐1‐deficient APC M in/+ mice developed three‐fold more adenomas than PAR‐1‐expressing mice, and the adenomas that formed were significantly larger. Moreover, loss of PAR‐1 expression was shown to limit apoptosis in transformed intestinal epithelial cells. Conclusions: Together, these results demonstrate a previously unrecognized role for PAR‐1 in impeding tumor progression in vivo . These results also offer a cautionary note suggesting that long‐term PAR‐1 inhibition could increase malignancy risk in some contexts.