- 作者: Chia-Chun Yu, Shih-Ping Liu, Jui-Ling Hsu, John TA Hsu, Konstantin V Kudryavtsev, Jih-Hwa Guh
- 作者服務機構: School of Pharmacy, National Taiwan University, Taipei, Taiwan R.O.C
- 中文摘要: --
- 英文摘要:
Background:
Hormone-refractory prostate cancer (HRPC), which is resistant to hormone therapy, is a major obstacle in clinical treatment. An approach to inhibit HRPC growth and ultimately to kill cancers is highly demanded.
Results:
KUD773 induced the anti-proliferative effect and subsequent apoptosis in PC-3 and DU-145 (two HRPC cell lines); whereas, it showed less active in normal prostate cells. Further examination showed that KUD773 inhibited tubulin polymerization and induced an increase of mitotic phosphoproteins and polo-like kinase 1 (PLK1) phosphorylation, indicating a mitotic arrest of the cell cycle through an anti-tubulin action. The kinase assay demonstrated that KUD773 inhibited Aurora A activity. KUD773 induced an increase of Cdk1 phosphorylation at Thr161 (a stimulatory phosphorylation site) and a decrease of phosphorylation at Tyr15 (an inhibitory phosphorylation
site), suggesting the activation of Cdk1. The data were substantiated by an up-regulation of cyclin B1 (a Cdk1 partner). Furthermore, KUD773 induced the phosphorylation and subsequent down-regulation of Bcl-2 and activation of caspase cascades.
Conclusions:
The data suggest that KUD773 induces apoptotic signaling in a sequential manner. It inhibits tubulin polymerization associated with an anti-Aurora A activity, leading to Cdk1 activation and mitotic arrest of the cell cycle
that in turn induces Bcl-2 degradation and a subsequent caspase activation in HRPCs. - 中文關鍵字: --
- 英文關鍵字: Hormone-refractory prostate cancer, Phenylthiazole derivative, Tubulin depolymerization, Aurora A kinase, Mitochondria-involved apoptosis