Inhibition of Akt survival pathway by a small-molecule inhibitor in human glioblastoma
Inhibition of Akt survival pathway by a small-molecule inhibitor in human glioblastoma
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DOI：
10.1158/1535-7163.mct-05-0453
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发表时间：
2006-03-01
影响因子：
5.7
通讯作者：
Yung, WKA
中科院分区：
文献类型：
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作者：
Koul, D;Shen, RJ;Yung, WKA
10号染色体上缺失的磷酸酶和张力蛋白同源物（PTEN）和Akt是磷脂酰肌醇3-激酶（PI 3 K）途径的重要调节剂，因此对于调节广泛的肿瘤相关生物学过程是重要的。Akt调节几种关键的细胞功能，包括细胞周期进展;细胞迁移、侵袭和存活;以及血管生成。在包括胶质母细胞瘤在内的多种癌症中，已经显示了PTEN表达的降低和Akt原癌基因的过表达，Akt原癌基因位于PI 3 K下游。受体和信号传导途径的新型小分子抑制剂，包括PI 3 K途径的抑制剂，已显示出抗肿瘤活性，但Akt的抑制剂尚未被检测。在这项研究中，我们验证了我们的假设，即药理学抑制Akt对胶质瘤具有抗增殖作用。我们发现两种新开发的Akt抑制剂KP-372-1和KP-372-2（本文称为KP-1和KP-2）有效地抑制PI 3 K/Akt信号级联。KP-1和KP-2在125和250 nmol/L时阻断了Akt Ser（473）的基础和表皮生长因子诱导的磷酸化，这反过来又减少了Akt的细胞内下游靶点的激活，包括GSK-3 β和p70 s6 k。此外，用125至250 nmol/L KP-1和KP 2处理U87和U251神经胶质瘤细胞48小时，抑制细胞生长约50%。这种细胞生长的减少源于细胞凋亡的诱导。总的来说，这些结果为Akt治疗神经胶质瘤的药理学靶向提供了强有力的理论基础。
Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and Akt are important regulators of the phosphatidylinositol 3-kinase (PI3K) pathway and thus are important to the regulation of a wide spectrum of tumor-related biological processes. Akt regulates several critical cellular functions, including cell cycle progression; cell migration, invasion, and survival; and angiogenesis. Decreased expression of PTEN and overexpression of the Akt proto-oncogene, which is located downstream of PI3K, have been shown in a variety of cancers, including glioblastoma. Novel small-molecule inhibitors of receptors and signaling pathways, including inhibitors of the PI3K pathway, have shown antitumor activity, but inhibitors of Akt have not been examined. In this study, we tested our hypothesis that the pharmacologic inhibition of Akt has an antiproliferative effect on gliomas. We showed that two newly developed Akt inhibitors, KP-372-1 and KP-372-2 (herein called KP-1 and KP-2), effectively inhibited the PI3K/Akt signaling cascade. KP-1 and KP-2 blocked both the basal and epidermal growth factor-induced phosphorylation of Akt Ser(473) at 125 and 250 nmol/L, which, in turn, reduced the activation of intracellular downstream targets of Akt, including GSK-3 beta and p70s6k. Furthermore, the treatment of U87 and U251 glioma cells with 125 to 250 nmol/L KP-1 and KP2 for 48 hours inhibited cell growth by similar to 50%. This decrease in cell growth stemmed from the induction of apoptosis. Collectively, these results provide a strong rationale for the pharmacologic targeting of Akt for the treatment of gliomas.