Yamaji Masayuki, Ota Akinobu, Wahiduzzaman Md, Karnan Sivasundaram, Hyodo Toshinori, Konishi Hiroyuki, Tsuzuki Shinobu, Hosokawa Yoshitaka, Haniuda Masayuki
Division of Chest Surgery, Department of Surgery, Aichi Medical University School of Medicine, Nagakute, Aichi, 480-1195, Japan.
Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Aichi, 480-1195, Japan.
Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
Malignant pleural mesothelioma (MPM), an asbestos-related occupational disease, is an aggressive and incurable tumor of the thoracic cavity. Despite recent advances in MPM treatment, overall survival of patients with MPM is very low. Recent studies have implicated that PI3K/Akt signaling is involved in MPM cell survival and development. To investigate the effects of Akt inhibitors on MPM cell survival, we examined the effects of nine selective Akt inhibitors, namely, afuresertib, Akti-1/2, AZD5363, GSK690693, ipatasertib, MK-2206, perifosine, PHT-427, and TIC10, on six MPM cell lines, namely, ACC-MESO-4, Y-MESO-8A, MSTO-211H, NCI-H28, NCI-H290, and NCI-H2052, and a normal mesothelial cell line MeT-5A. Comparison of IC values of the Akt inhibitors showed that afuresertib, an ATP-competitive specific Akt inhibitor, exerted tumor-specific effects on MPM cells. Afuresertib significantly increased caspase-3 and caspase-7 activities and apoptotic cell number among ACC-MESO-4 and MSTO-211H cells. Moreover, afuresertib strongly arrested the cell cycle in the G phase. Western blotting analysis showed that afuresertib increased the expression of p21 and decreased the phosphorylation of Akt substrates, including GSK-3β and FOXO family proteins. These results suggest that afuresertib-induced p21 expression promotes G phase arrest by inducing FOXO activity. Furthermore, afuresertib significantly enhanced cisplatin-induced cytotoxicity. Interestingly, results of gene set enrichment analysis showed that afuresertib modulated the expression E2F1 and MYC, which are associated with fibroblast core serum response. Together, these results suggest that afuresertib is a useful anticancer drug for treating patients with MPM.
恶性胸膜间皮瘤（MPM）是一种与石棉相关的职业病，是一种侵袭性且无法治愈的胸腔肿瘤。尽管MPM治疗最近取得了进展，但MPM患者的总体生存率仍然很低。最近的研究表明，PI3K/Akt信号通路参与MPM细胞的存活和发展。为了研究Akt抑制剂对MPM细胞存活的影响，我们检测了九种选择性Akt抑制剂，即阿福司替尼、Akti-1/2、AZD5363、GSK690693、依帕司他、MK-2206、哌立福辛、PHT-427和TIC10，对六种MPM细胞系，即ACC-MESO-4、Y-MESO-8A、MSTO-211H、NCI-H28、NCI-H290和NCI-H2052，以及一种正常间皮细胞系MeT-5A的影响。Akt抑制剂IC值的比较表明，阿福司替尼作为一种ATP竞争性特异性Akt抑制剂，对MPM细胞具有肿瘤特异性作用。阿福司替尼显著增加了ACC-MESO-4和MSTO-211H细胞中caspase-3和caspase-7的活性以及凋亡细胞数量。此外，阿福司替尼强烈地将细胞周期阻滞在G期。蛋白质印迹分析表明，阿福司替尼增加了p21的表达，并降低了包括GSK-3β和FOXO家族蛋白在内的Akt底物的磷酸化。这些结果表明，阿福司替尼诱导的p21表达通过诱导FOXO活性促进G期阻滞。此外，阿福司替尼显著增强了顺铂诱导的细胞毒性。有趣的是，基因集富集分析结果表明，阿福司替尼调节了与成纤维细胞核心血清反应相关的E2F1和MYC的表达。总之，这些结果表明阿福司替尼是一种治疗MPM患者的有用抗癌药物。
