Thrombin inhibits tumor cell growth in association with up-regulation of p21(waf/cip1) and caspases via a p53-independent, STAT-1-dependent pathway

Citation
Yq. Huang et al., Thrombin inhibits tumor cell growth in association with up-regulation of p21(waf/cip1) and caspases via a p53-independent, STAT-1-dependent pathway, J BIOL CHEM, 275(9), 2000, pp. 6462-6468
Citations number
38
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
0021-9258 → ACNP
Volume
275
Issue
9
Year of publication
2000
Pages
6462 - 6468
Database
ISI
SICI code
0021-9258(20000303)275:9<6462:TITCGI>2.0.ZU;2-2
Abstract
Thrombin, a multifunctional protein, has been found to be involved in cellu lar mitogenesis, tumor growth, and metastasis, in addition to its well know n effects on the initiation of platelet aggregation and secretion and the c onversion of fibrinogen to fibrin to form blood clots. These properties of thrombin rely on its action as a serine protease, which cleaves the N-termi nal region of a 7-transmembrane G protein receptor (protease-activated rece ptor, PAR-1), thus exposing a tethered end hexapeptide sequence capable of activating its receptor. Little is known about its effect on genes that reg ulate the cell cycle. This study was undertaken to investigate the possible mechanisms by which thrombin regulates tumor cell growth in several tumor cell lines: human CHRF megakaryocyte, DU145 prostate, MDAMB231 and MCF7 bre ast, U3A fibrosarcoma, and 2 murine fibroblast cell lines, MEFp53(-/-) and CD STAT(-/-), We have found that thrombin under the conditions of culture e mployed inhibits cell growth by both up-regulation of p21(waf/cip1) and ind uction of caspases via its PAR-1 receptor. The increased expression of p21( waf/cip1) by thrombin was p53 independent, STAT1 dependent, and protein syn thesis independent. This was associated with tyrosine phosphorylation of JA K2 and STAT1, and nuclear translocation of STAT1, Induction of apoptosis is also PAR-1-specific, STAT1-dependent, and associated with up-regulation of caspases 1, 2, and 3. Our study establishes, for the first time, a link be tween PAR-1 receptor activation with the STAT signal pathway, which leads t o cell cycle control and apoptosis. This observation broadens our understan ding of the mechanism of PAR-1 activation and its effect on cell growth, an d could possibly lead to therapeutic approaches for the treatment of cancer .