期刊
ONCOGENE
卷 21, 期 11, 页码 1727-1738出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1205225
关键词
UCN-01; PDK1; Akt; apoptosis; PKC
3-Phosphoinositide-dependent protein kinase-1 (PDKI) plays a central role in activating the AGC subfamily of protein kinases. In particular, PDKI plays an important role in the regulation of Akt/PKB survival pathway by phosphorylating Akt on Thr(308). Here we show that UCN-01 (7-hydroxystaurosporine), a drug now in clinical trials and with a unique fingerprint pattern, induced dephosphorylation and inactivation of Akt, resulting in the turnoff of the survival signals and the induction of apoptosis. Further analysis revealed that UCN-01-mediated Akt inactivation was caused by inhibiting upstream Akt kinase PDKI (IC50=33 nm) both in vitro and from cells, but not by suppressing Akt itself or phosphatidylinositide-3-OH kinase. UCN-01-induced PDKI inhibition was also observed in in vivo murine and human tumor xenografts. Overexpression of active form of Akt diminished the cytotoxic effects of UCN-01, suggesting that UCN-01 may in part exert its cytotoxicity by inhibiting PDKI-Akt survival pathway. Because UCN-01 has already proved to have potent anti-tumor activity in vivo, PDKI-Akt survival pathway is a new, attractive target for cancer chemotherapy.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据