Mao Mintao, Liu Yumei, Gao Xinhai
Emergency Center, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Emergency Center, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Biochem Biophys Res Commun. 2017 Sep 2;490(4):1244-1249. doi: 10.1016/j.bbrc.2017.07.002. Epub 2017 Jul 1.
The current study evaluated the potential anti-colorectal cancer (CRC) activity by Ku-0060648, a novel DNA-PKcs and PI3K duel inhibitor. In both CRC cell lines (HCT-116 and HT-29) and primary human colon cancer cells, Ku-0060648 exposure at nM concentrations efficiently inhibited cell proliferation. Meanwhile, Ku-0060648 provoked apoptosis in CRC cells. Ku-0060648 was yet ineffective to the normal colon epithelial cells. Ku-0060648 blocked PI3K-AKT-mTOR cascade and in-activated DNA-PKcs in CRC cells. Intriguingly, Ku-0060648 treatment induced feedback autophagy activation in HCT-116 cells. On the other hand, pharmacological autophagy inhibitors (3-methyladenine or chloroquine) or silencing key autophagy proteins (Beclin-1 or ATG-7) dramatically potentiated Ku-0060648-induced HCT-116 cell apoptosis. Together, these results suggest that feedback autophagy activation is a key resistance factor of Ku-0060648 in CRC cells, and autophagy inhibition sensitizes Ku-0060648-induced anti-CRC activity.
本研究评估了新型DNA-PKcs和PI3K双重抑制剂Ku-0060648潜在的抗结直肠癌（CRC）活性。在结直肠癌细胞系（HCT-116和HT-29）以及原代人结肠癌细胞中，纳摩尔浓度的Ku-0060648能够有效抑制细胞增殖。同时，Ku-0060648可诱导结直肠癌细胞凋亡。而Ku-0060648对正常结肠上皮细胞无效。Ku-0060648可阻断结直肠癌细胞中的PI3K-AKT-mTOR级联反应并使DNA-PKcs失活。有趣的是，Ku-0060648处理可诱导HCT-116细胞发生反馈性自噬激活。另一方面，药理学自噬抑制剂（3-甲基腺嘌呤或氯喹）或沉默关键自噬蛋白（Beclin-1或ATG-7）可显著增强Ku-0060648诱导的HCT-116细胞凋亡。总之，这些结果表明反馈性自噬激活是Ku-0060648在结直肠癌细胞中的关键耐药因素，而抑制自噬可使Ku-0060648诱导的抗结直肠癌活性增敏。
