Interference with PDK1-Akt survival signaling pathway by UCN-01 (7-hydroxystaurosporine)
Interference with PDK1-Akt survival signaling pathway by UCN-01 (7-hydroxystaurosporine)
复制标题
DOI：
10.1038/sj.onc.1205225
复制
发表时间：
2002-03-07
期刊：
影响因子：
8
通讯作者：
Tsuruo, T
中科院分区：
文献类型：
--
作者：
Sato, S;Fujita, N;Tsuruo, T
3-磷酸肌醇依赖性蛋白激酶-1（PDKI）在激活蛋白激酶的AGC亚家族中起核心作用。特别是PDKI通过磷酸化Thr（308）上的Akt在Akt/PKB存活途径的调节中起重要作用。在这里，我们表明，UCN-01（7-hydroxystaurosporine），目前在临床试验中的药物，并具有独特的指纹图谱，诱导Akt的去磷酸化和失活，导致关闭的生存信号和诱导细胞凋亡。进一步的分析表明，UCN-01介导的Akt失活是通过抑制上游Akt激酶PDKI（IC 50 =33 nm）在体外和细胞，但不是通过抑制Akt本身或磷脂酰肌醇-3-OH激酶。在体内鼠和人肿瘤异种移植物中也观察到UCN-01诱导的PDKI抑制。Akt活性形式的过表达减弱了UCN-01的细胞毒性作用，表明UCN-01可能部分通过抑制PDKI-Akt存活途径发挥其细胞毒性作用。由于UCN-01已经被证明具有有效的体内抗肿瘤活性，PDKI-Akt存活通路是一个新的、有吸引力的癌症化疗靶点。
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.