Wang Siyu, Li Jie, Du Yanyun, Xu Yujia, Wang Yali, Zhang Zubin, Xu Zhuan, Zeng Yuanying, Mao Xinliang, Cao Biyin
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China; Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, China.
J Pharmacol Sci. 2017 Aug;134(4):197-202. doi: 10.1016/j.jphs.2017.07.001. Epub 2017 Jul 19.
S14161 is a pan-Class I PI3K inhibitor that induces blood cancer cell death, but its mechanism is largely unknown. In the present study, we evaluated the role of S14161 in autophagy, an emerging event in cell destination. Multiple myeloma cell lines RPMI-8226, OPM2, KMS11 and leukemia cell line K562 were treated with S14161. The results showed that S14161 induced autophagy as demonstrated by increased LC3-II and decreased p62, which were prevented by autophagy inhibitors including 3-methyladenine and bafilomycin A1. Mechanistic studies showed that S14161 had no effects on Vps34 expression, but increased Beclin 1 and decreased Bcl-2, two major regulators of autophagy. Furthermore, S14161 dissociated the Beclin 1/Bcl-2 complex and enhanced the formation of Beclin 1/Vps34 complex. Moreover, S14161 inhibited the mTORC1 signaling transduction. S14161 downregulated activation of mTOR and its two critical targets 4E-BP1 and p70S6K, suggesting S14161 inhibited protein synthesis. Taken together, these results demonstrated that Class I PI3K regulates autophagy by modulating protein synthesis and the Beclin 1 signaling pathway. This finding helps understanding the roles of PI3K in autophagy and cancer treatment.
S14161是一种泛I类PI3K抑制剂，可诱导血癌细胞死亡，但其机制尚不清楚。在本研究中，我们评估了S14161在自噬（细胞命运中的一个新现象）中的作用。用S14161处理多发性骨髓瘤细胞系RPMI-8226、OPM2、KMS11和白血病细胞系K562。结果显示，S14161诱导自噬，表现为LC3-II增加和p62减少，而3-甲基腺嘌呤和巴弗洛霉素A1等自噬抑制剂可阻止这种情况。机制研究表明，S14161对Vps34表达没有影响，但增加了Beclin 1并降低了Bcl-2，这是自噬的两个主要调节因子。此外，S14161使Beclin 1/Bcl-2复合物解离，并增强了Beclin 1/Vps34复合物的形成。此外，S14161抑制mTORC1信号转导。S14161下调mTOR及其两个关键靶点4E-BP1和p70S6K的激活，表明S14161抑制蛋白质合成。综上所述，这些结果表明I类PI3K通过调节蛋白质合成和Beclin 1信号通路来调节自噬。这一发现有助于理解PI3K在自噬和癌症治疗中的作用。
