Inhibition of PIKfyve using YM201636 suppresses the growth of liver cancer via the induction of autophagy
Inhibition of PIKfyve using YM201636 suppresses the growth of liver cancer via the induction of autophagy
复制标题
使用 YM201636 抑制 PIKfyve 通过诱导自噬抑制肝癌的生长
DOI：
10.3892/or.2018.6928
复制
发表时间：
2019-03-01
期刊：
影响因子：
4.2
通讯作者：
Xie, Song-Qiang
中科院分区：
文献类型：
--
作者：
Hou, Jiu-Zhou;Xi, Zhuo-Qing;Xie, Song-Qiang
肝癌是全世界最常见的癌症类型之一。本研究的目的是研究磷脂酰肌醇-3-磷酸5-激酶（PIKfyve）抑制剂YM201636是否对肝癌具有抗增殖作用。本研究使用的方法包括MTT测定、流式细胞术、蛋白质印迹分析和肝癌同种异体移植小鼠模型。结果显示，YM201636以剂量依赖性方式抑制HepG2和Huh-7细胞的增殖。用 YM201636 处理后，HepG2 和 Huh-7 细胞表现出强烈的单丹酰尸胺染色。因此，YM201636 处理增加了 HepG2 和 Huh-7 细胞中自噬体相关标记蛋白微管相关 1A/1B 轻链 3-II 的表达。自噬抑制剂3-甲基腺嘌呤减弱了YM201636对肝癌细胞增殖的抑制作用。进一步的体内分析表明，YM201636 (2 mg/kg) 可抑制肿瘤生长，且没有明显的全身毒性。机制实验表明，YM201636 诱导的自噬依赖于 HepG2 和 Huh-7 细胞中表皮生长因子受体 (EGFR) 的过度表达。总的来说，这些结果表明 PIKfyve 抑制剂 YM201636 可能通过促进 EGFR 表达来抑制肿瘤生长。这表明PIKfyve可能是治疗肝癌的潜在治疗靶点。
Liver cancer is among the most common types of cancer worldwide. The aim of the present study was to investigate whether the phosphatidylinositol-3-phosphate 5-kinase (PIKfyve) inhibitor, YM201636, exerts anti-proliferative effects on liver cancer. The methods used in the present study included MTT assay, flow cytometry, western blot analysis and an allograft mouse model of liver cancer. The results revealed that YM201636 inhibited the proliferation of HepG2 and Huh-7 cells in a dose-dependent manner. HepG2 and Huh-7 cells exhibited strong monodansylcadaverine staining following treatment with YM201636. Accordingly, YM201636 treatment increased the expression of the autophagosome-associated marker protein microtubule-associated 1A/1B light chain 3-II in HepG2 and Huh-7 cells. The autophagy inhibitor 3-methyladenine attenuated the inhibitory effects of YM201636 on liver cancer cell proliferation. Further in vivo analysis revealed that YM201636 (2 mg/kg) inhibited tumor growth without notable systemic toxicity. Mechanistic experiments demonstrated that YM201636 induced-autophagy is dependent upon epidermal growth factor receptor (EGFR) overexpression in HepG2 and Huh-7 cells. Collectively, these results suggested that the PIKfyve inhibitor YM201636 may inhibit tumor growth by promoting EGFR expression. This indicates that PIKfyve may be a potential therapeutic target for the treatment of liver cancer.