Blocking AMPK/ULK1-dependent autophagy promoted apoptosis and suppressed colon cancer growth
Blocking AMPK/ULK1-dependent autophagy promoted apoptosis and suppressed colon cancer growth
复制标题
阻断 AMPK/ULK1 依赖性自噬促进细胞凋亡并抑制结肠癌生长
DOI：
10.1186/s12935-019-1054-0
复制
发表时间：
2019-12-13
影响因子：
5.8
通讯作者：
Zhang, Yingjie
中科院分区：
文献类型：
--
作者：
Liu, Jing;Long, Shuaiyu;Zhang, Yingjie
背景自噬是一个进化上保守的细胞降解和回收胞质的过程。方法采用CCK 8、结晶紫染色、Hoechst 333342染色和流式细胞术检测细胞活力和凋亡。Western blotting检测AMPK和ULK 1的表达。NVP-BEZ 235或CQ在体内对结肠癌生长的抑制作用在肿瘤异种移植小鼠模型中进行了研究。ResultsOur先前的研究表明，NVP-BEZ 235通过诱导细胞凋亡抑制结肠癌生长，但后来，我们发现它也同时启动自噬。在本研究中，我们的结果表明NVP-BEZ 235通过AMPK/ULK 1途径诱导结肠癌细胞的自噬。通过敲低AMPK或ULK 1阻断自噬抑制细胞增殖并进一步促进NVP-BEZ 235诱导的凋亡。自噬抑制剂氯喹（chloroquine，CQ）对细胞增殖有明显的抑制作用，但对细胞凋亡无明显诱导作用，而对NVP-BEZ 235诱导的细胞凋亡有明显的促进作用。结论NVP-BEZ 235可诱导AMPK/ULK 1依赖性自噬。针对这种自噬通过进一步促进细胞凋亡来抑制结肠癌的生长，这是临床患者的潜在治疗选择。
BackgroundAutophagy is an evolutionarily conserved process through which cells degrade and recycle cytoplasm. The relation among autophagy, apoptosis and tumor is highly controversial until now and the molecular mechanism is poorly understood.MethodsCell viability and apoptosis were detected by CCK8, crystal violet staining, Hoechst333342 staining and flow cytometry. The expression of AMPK and ULK1 was analyzed by western blotting. Colon cancer growth suppression by NVP-BEZ235 or CQ in vivo was studied in a tumor xenograft mouse model.ResultsOur previous study revealed that NVP-BEZ235 suppressed colorectal cancer growth via inducing apoptosis, however later, we found it also initiated autophagy simultaneously. In this present study, our results show that NVP-BEZ235 induced autophagy through AMPK/ULK1 pathway in colon cancer cells. Blocking autophagy by knocking down AMPK or ULK1 inhibited cell proliferation and further promoted NVP-BEZ235 induced apoptosis. Meantime, the autophagy inhibitor chloroquine (CQ) shows obvious effect on inhibiting cell proliferation but not on inducing apoptosis, while it significantly increased NVP-BEZ235 induced apoptosis. Furthermore, the combinational therapy of NVP-BEZ235 and CQ shows synergistic antitumor effects in colon cancer in vivo.ConclusionNVP-BEZ235 induced AMPK/ULK1-dependent autophagy. Targeting this autophagy suppressed colon cancer growth through further promoting apoptosis, which is a potential therapeutic option for clinical patients.