Protease-activated receptor-1 impedes prostate and intestinal tumor progression in mice.
Protease-activated receptor-1 impedes prostate and intestinal tumor progression in mice.
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DOI：
10.1111/jth.14277
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发表时间：
2018-11
期刊：
影响因子：
--
通讯作者：
Palumbo JS
中科院分区：
文献类型：
--
作者：
Adams GN;Sharma BK;Rosenfeldt L;Frederick M;Flick MJ;Witte DP;Mosnier LO;Harmel-Laws E;Steinbrecher KA;Palumbo JS
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. We analyzed the role of PAR-1 in the setting of two distinct spontaneously developing tumor models in mice. We interbred PAR-1-deficient mice with TRAMP (Transgenic Adenocarcinoma of the Mouse Prostate) mice, which spontaneously develop prostate tumors, and adenomatous polyposis coli Min (APCMin/+) mice, which spontaneously develop intestinal adenomas. 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 tumor cell intrinsic PAR-1 functions can limit tumor progression. Paralleling results in TRAMP mice, PAR-1-deficient APCMin/+ mice developed 3-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. 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.
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影响因子：
11.2
作者：
Adams GN;Rosenfeldt L;Frederick M;Miller W;Waltz D;Kombrinck K;McElhinney KE;Flick MJ;Monia BP;Revenko AS;Palumbo JS
通讯作者：
Palumbo JS
影响因子：
4.8
作者：
Mihara, Koichiro;Ramachandran, Rithwik;Hollenberg, Morley D.
通讯作者：
Hollenberg, Morley D.
影响因子：
3.7
作者：
Fazzini, Alessandra;D'Antongiovanni, Vanessa;Mazzoni, Maria Rosa
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Mazzoni, Maria Rosa
影响因子：
2.8
作者：
Kaushal, V;Kohli, M;Mukunyadzi, P
通讯作者：
Mukunyadzi, P
影响因子：
6.4
作者：
Queiroz, Karla C. S.;Shi, Kun;Spek, C. Arnold
通讯作者：
Spek, C. Arnold