Sato Saori, Fujita Naoya, Tsuruo Takashi
Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan.
Oncogene. 2002 Mar 7;21(11):1727-38. doi: 10.1038/sj.onc.1205225.
3-Phosphoinositide-dependent protein kinase-1 (PDK1) plays a central role in activating the AGC subfamily of protein kinases. In particular, PDK1 plays an important role in the regulation of Akt/PKB survival pathway by phosphorylating Akt on Thr308. 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 turn-off 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 PDK1 (IC50=33 nM) both in vitro and from cells, but not by suppressing Akt itself or phosphatidylinositide-3-OH kinase. UCN-01-induced PDK1 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 PDK1-Akt survival pathway. Because UCN-01 has already proved to have potent anti-tumor activity in vivo, PDK1-Akt survival pathway is a new, attractive target for cancer chemotherapy.
3-磷酸肌醇依赖性蛋白激酶-1（PDK1）在激活蛋白激酶的AGC亚家族中起着核心作用。特别是，PDK1通过在苏氨酸308位点磷酸化Akt，在Akt/PKB存活途径的调节中发挥重要作用。在此我们表明，UCN-01（7-羟基星孢菌素），一种目前正在进行临床试验且具有独特指纹图谱的药物，可诱导Akt去磷酸化并使其失活，导致存活信号关闭并诱导细胞凋亡。进一步分析表明，UCN-01介导的Akt失活是由于在体外和细胞中抑制上游Akt激酶PDK1（IC50 = 33 nM）所致，而非通过抑制Akt本身或磷脂酰肌醇-3-OH激酶。在体内小鼠和人肿瘤异种移植模型中也观察到了UCN-01诱导的PDK1抑制作用。活性形式的Akt过表达减弱了UCN-01的细胞毒性作用，这表明UCN-01可能部分通过抑制PDK1-Akt存活途径发挥其细胞毒性。由于UCN-01已在体内被证明具有强大的抗肿瘤活性，PDK1-Akt存活途径是癌症化疗一个新的、有吸引力的靶点。
