Dual PI3K/mTOR inhibitor NVP-BEZ235-induced apoptosis of hepatocellular carcinoma cell lines is enhanced by inhibitors of autophagy
Dual PI3K/mTOR inhibitor NVP-BEZ235-induced apoptosis of hepatocellular carcinoma cell lines is enhanced by inhibitors of autophagy
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DOI：
10.3892/ijmm.2013.1351
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发表时间：
2013-06-01
影响因子：
5.4
通讯作者：
Jia, Xiaojing
中科院分区：
文献类型：
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作者：
Chang, Zhexing;Shi, Guang;Jia, Xiaojing
磷脂酰肌醇3-激酶(PI3K)/AKT/哺乳动物雷帕霉素靶标(MTOR)信号通路的失调在包括肝细胞癌(HCC)在内的多种人类癌症中被发现。NVP-BEZ235是一种新型的口服生物利用型双PI3K/mTOR抑制剂，在临床前模型中显示出良好的抗肝癌活性。自噬是一种细胞溶酶体降解途径，对于调节细胞存活和死亡以维持内稳态是必不可少的。这一过程受到mTOR信号的负面调控，并经常抵消某些癌症治疗药物的疗效。在本研究中，我们探讨了自噬在NVP-BEZ235诱导肝癌细胞株Hep3B和PLC/PRF/5凋亡中的作用，并探讨了联合作用的机制。NVP-BEZ235对两种肝癌细胞的生长有抑制作用，其机制可能与诱导细胞凋亡有关。NVP-BEZ235还能显著增加Lc3-II的表达，降低p62的表达，提示自噬的发生。当NVP-BEZ235与ATG5 siRNA或自噬抑制剂3-甲基腺嘌呤(3-MA)联合使用时，对肝癌细胞的生长抑制作用增强。此外，NVP-BEZ235与ATG5 siRNA或3-MA联合作用可增强细胞的凋亡诱导作用。因此，NVP-BEZ235诱导自噬可能是抵消其抗癌作用的一种生存机制。基于这些数据，我们提出了通过阻断自噬来增强BEZ235的抗癌效果的策略。因此，我们的研究为NVP-BEZ235和自噬抑制剂联合治疗肝癌和其他恶性肿瘤的临床开发提供了理论基础。
Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling has been found in several types of human cancer, including hepatocellular carcinoma (HCC). NVP-BEZ235 is a novel, orally bioavailable dual PI3K/mTOR inhibitor that has exhibited promising activity against HCC in preclinical models. Autophagy is a cellular lysosomal degradation pathway essential for the regulation of cell survival and death to maintain homeostasis. This process is negatively regulated by mTOR signaling and often counteracts the efficacy of certain cancer therapeutic agents. In this study, we explored the role of autophagy in apoptosis induced by NVP-BEZ235 in two HCC cell lines, Hep3B and PLC/PRF/5, and identified the mechanism of combinatorial treatment. NVP-BEZ235 was effective in inhibiting the growth of the two HCC cell lines possibly though induction of apoptosis. NVP-BEZ235 also potently increased the expression of LC3-II and decreased the expression of p62, indicating induction of autophagy. When NVP-BEZ235 was used in combination with Atg5 siRNA or the autophagy inhibitor 3-methyladenine (3-MA), enhancement of the inhibitory effects on the growth of HCC cells was detected. In addition, enhanced induction of apoptosis was observed in cells exposed to the combination of NVP-BEZ235 and Atg5 siRNA or 3-MA. Thus, induction of autophagy by NVP-BEZ235 may be a survival mechanism that counteracts its anticancer effects. Based on these data, we suggest a strategy to enhance the anticancer efficacy of BEZ235 by blockade of autophagy. Thus, our study provides a rationale for the clinical development of combinations of NVP-BEZ235 and autophagy inhibitors for the treatment of HCC and other malignancies.