medicine |
examination of the effect of thrombin on tumor cell cycle activation and spontaneous growth in synchronized serum-starved tumor cell lines and a model of spontaneous prostate cancer development in TRAMP mice expressing the SV40 Large T Antigen under the control of the prostate-specific probasin promoter, leading to the spontaneous development of prostate cancer and metastasis. Prostate LNCaP cells arrested in G0 and treated with thrombin or serum reveal a 48- and 29-fold increase in S phase cells, respectively, at 8 hours. Addition of thrombin, PAR-1 agonist TFLLRN, or serum down-regulates the inhibitory cell cycle regulator p27Kip1 with concomitant induction of Skp2, cyclin D1, and cyclin A with similar kinetics. LNCaP p27Kip1-transfected cells or Skp2 knockdown cells are refractory to thrombin-induced cell cycle activation. Repetitive thrombin injection enhances prostate tumor volume 6- to 8-fold. Repetitive hirudin injection, a specific potent antithrombin, decreases tumor volume 13- to 24fold |
Homo sapiens |