Enzastaurin, a protein kinase Cβ inhibitor, suppresses signaling through the ribosomal S6 kinase and bad pathways and induces apoptosis in human gastric cancer
Enzastaurin, a protein kinase Cβ inhibitor, suppresses signaling through the ribosomal S6 kinase and bad pathways and induces apoptosis in human gastric cancer
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DOI：
10.1158/0008-5472.can-07-3195
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发表时间：
2008-03-15
期刊：
影响因子：
11.2
通讯作者：
Bang, Yung-Jue
中科院分区：
文献类型：
--
作者：
Lee, Keun-Wook;Kim, Sang Gyun;Bang, Yung-Jue
蛋白激酶C（PKC）的激活与胃癌发生有关。 Enzastaurin是PKCβ同工酶的口服ATP竞争力抑制剂。尽管Enzastaurin最初是根据其抗血管生成活性前进到诊所的，但众所周知，它对多种人类癌细胞具有直接影响，从而通过抑制AKT信号途径诱导凋亡。但是，胃癌的enzastaurin数据受到限制。因此，进行了这项研究以评估恩扎斯陶蛋白对胃癌细胞的抗肿瘤活性并研究潜在的抗肿瘤机制。 Enzastaurin抑制了培养的胃癌细胞的增殖和胃癌异种移植物的生长。 Enzastaurin对胃癌细胞周期的进展没有影响。但是，它通过caspase介导的线粒体途径具有直接的凋亡诱导作用。糖原合酶激酶激酶30磷酸化，Enzastaurin活性的可靠药效标记和Akt磷酸化磷酸化均均降低了，两者都在用Enzastaurin治疗后降低。尽管p90核糖体S6激酶（RSK）也被脱磷酸化，但在Enzastaurin治疗的胃癌细胞中不影响ERK磷酸化。 Enzastaurin通过在SER（112）的去磷酸化（112）的去磷酸化激活的BAD，这是Bcl-2促凋亡蛋白之一，不良活性的耗竭导致胃癌细胞中Enzastaurin诱导的细胞凋亡和细胞毒性的抗性。这些数据表明，除了抑制Akt信号级联反应外，Enzastaurin通过RSK介导的和坏介导的途径诱导凋亡。此外，与5-氟尿嘧啶，顺铂，紫杉醇或伊立替康相结合时，Enzastaurin具有协同或加性效应。这些结果值得对Enzastaurin进行胃癌治疗的进一步临床研究。
Activation of protein kinase C (PKC) has been implicated in gastric carcinogenesis. Enzastaurin is an oral ATP-competitive inhibitor of the PKC beta isozyme. Although enzastaurin was initially advanced to the clinic based on its antiangiogenic activity, it is also known to have a direct effect on a variety of human cancer cells, inducing apoptosis by inhibiting the Akt signal pathway. However, data on enzastaurin for gastric cancer are limited. Therefore, this study was performed to assess the antitumor activity of enzastaurin on gastric cancer cells and to investigate the underlying antitumor mechanisms. Enzastaurin suppressed the proliferation of cultured gastric cancer cells and the growth of gastric carcinoma xenografts. Enzastaurin did not have an effect on gastric cancer cell cycle progression; however, it had a direct apoptosis-inducing effect through the caspase-mediated mitochondrial pathway. Glycogen synthase kinase 30 phosphorylation, a reliable pharmacodynamic marker of enzastaurin activity, and Akt phosphorylation were both decreased after treatment with enzastaurin. Although the p90 ribosomal S6 kinase (Rsk) was also dephosphorylated, Erk phosphorylation was not affected in the enzastaurin-treated gastric cancer cells. Enzastaurin activated Bad, one of the Bcl-2 proapoptotic proteins, through dephosphorylation at Ser(112), and depletion of Bad activity resulted in resistance to enzastaurin-induced apoptosis and cytotoxicity in gastric cancer cells. These data suggest that enzastaurin induces apoptosis through Rsk-mediated and Bad-mediated pathways, besides inhibiting the Akt signal cascade. Furthermore, enzastaurin had synergistic or additive effects when combined with 5-fluorouracil, cisplatin, paclitaxel, or irinotecan. These results warrant further clinical investigation of enzastaurin for gastric cancer treatment.