Yuan Chun-Xiu, Zhou Zhi-Wei, Yang Yin-Xue, He Zhi-Xu, Zhang Xueji, Wang Dong, Yang Tianxing, Wang Ning-Ju, Zhao Ruan Jin, Zhou Shu-Feng
Department of Oncology, General Hospital Ningxia Medical University, Yinchuan, Ningxia, People's Republic of China ; Department of Pharmaceutical Science, College of Pharmacy, University of South Florida, Tampa, FL, USA.
Department of Pharmaceutical Science, College of Pharmacy, University of South Florida, Tampa, FL, USA ; Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, People's Republic of China.
Drug Des Devel Ther. 2015 Jan 14;9:487-508. doi: 10.2147/DDDT.S74127. eCollection 2015.
Gastric cancer is one of the most common cancers and responds poorly to current chemotherapy. Alisertib (ALS) is a second-generation, orally bioavailable, highly selective small-molecule inhibitor of the serine/threonine protein kinase Aurora kinase A (AURKA). ALS has been shown to have potent anticancer effects in preclinical and clinical studies, but its role in gastric cancer treatment is unclear. This study aimed to investigate the cancer cell-killing effect of ALS on gastric cancer cell lines AGS and NCI-N78, with a focus on cell proliferation, cell-cycle distribution, apoptosis, and autophagy and the mechanism of action. The results showed that ALS exhibited potent growth-inhibitory, proapoptotic, and proautophagic effects on AGS and NCI-N78 cells. ALS concentration-dependently inhibited cell proliferation and induced cell-cycle arrest at G2/M phase in both cell lines, with a downregulation of cyclin-dependent kinase 1 and cyclin B1 expression but upregulation of p21 Waf1/Cip1, p27 Kip1, and p53 expression. ALS induced mitochondria-mediated apoptosis and autophagy in both AGS and NCI-N78 cells. ALS induced the expression of proapoptotic proteins but inhibited the expression of antiapoptotic proteins, with a significant increase in the release of cytochrome c and the activation of caspase 9 and caspase 3 in both cell lines. ALS induced inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase (MAPK) signaling pathways while activating the 5'-adenosine monophosphate-activated protein kinase (AMPK) signaling pathway as indicated by their altered phosphorylation, contributing to the proautophagic effects of ALS. SB202191 and wortmannin enhanced the autophagy-inducing effect of ALS in AGS and NCI-N78 cells. Notably, ALS treatment significantly decreased the ratio of phosphorylated AURKA over AURKA, which may contribute, at least in part, to the inducing effects of ALS on cell-cycle arrest and autophagy in AGS and NCI-N78 cells. Taken together, these results indicate that ALS exerts a potent inhibitory effect on cell proliferation but inducing effects on cell-cycle arrest, mitochondria-dependent apoptosis, and autophagy with the involvement of PI3K/Akt/mTOR, p38 MAPK, and AURKA-mediated signaling pathways in AGS and NCI-N78 cells.
胃癌是最常见的癌症之一，对当前的化疗反应不佳。阿利西替尼（ALS）是第二代口服生物可利用的、高度选择性的丝氨酸/苏氨酸蛋白激酶极光激酶A（AURKA）小分子抑制剂。在临床前和临床研究中，ALS已显示出有强大的抗癌作用，但其在胃癌治疗中的作用尚不清楚。本研究旨在探讨ALS对胃癌细胞系AGS和NCI-N78的癌细胞杀伤作用，重点关注细胞增殖、细胞周期分布、凋亡和自噬以及作用机制。结果表明，ALS对AGS和NCI-N78细胞表现出强大的生长抑制、促凋亡和促自噬作用。ALS浓度依赖性地抑制两种细胞系的细胞增殖并诱导细胞周期停滞在G2/M期，同时下调细胞周期蛋白依赖性激酶1和细胞周期蛋白B1的表达，但上调p21 Waf1/Cip1、p27 Kip1和p53的表达。ALS在AGS和NCI-N78细胞中均诱导线粒体介导的凋亡和自噬。ALS诱导促凋亡蛋白的表达，但抑制抗凋亡蛋白的表达，两种细胞系中细胞色素c的释放以及半胱天冬酶9和半胱天冬酶3的激活均显著增加。ALS诱导磷脂酰肌醇3激酶（PI3K）/蛋白激酶B（Akt）/雷帕霉素哺乳动物靶蛋白（mTOR）和p38丝裂原活化蛋白激酶（MAPK）信号通路的抑制，同时激活5'-腺苷单磷酸激活蛋白激酶（AMPK）信号通路，这可通过它们磷酸化的改变来表明，这有助于ALS的促自噬作用。SB202191和渥曼青霉素增强了ALS在AGS和NCI-N78细胞中的自噬诱导作用。值得注意的是，ALS处理显著降低了磷酸化AURKA与AURKA的比率，这可能至少部分地促成了ALS对AGS和NCI-N78细胞的细胞周期停滞和自噬的诱导作用。综上所述，这些结果表明ALS对细胞增殖发挥强大的抑制作用，但在AGS和NCI-N78细胞中通过PI3K/Akt/mTOR、p38 MAPK和AURKA介导的信号通路参与对细胞周期停滞、线粒体依赖性凋亡和自噬产生诱导作用。
Zotero 插件
