机构：[1]Department of Oncology, Kunshan First People’s Hospital Affiliated to Jiangsu University, Kunshan 215300, China[2]Department of Orthopedics, the Second Affiliated Hospital of Soochow University, Suzhou 215000, China[3]Department of Breast Surgery, the Third Affiliated Hospital of Soochow University, Changzhou 213003, China[4]Department of Traditional Chinese Medicine, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China[5]Department of Medical Oncology, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi 214023, China[6]Department of Neurosurgery, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
Here we tested anti-tumor activity of KU-0060648 in preclinical hepatocellular carcinoma (HCC) models. Our results demonstrated that KU-0060648 was anti-proliferative and pro-apoptotic in established (HepG2, Huh-7 and KYN-2 lines) and primary human HCC cells, but was non-cytotoxic to non-cancerous HL-7702 hepatocytes. DNA-PKcs (DNA-activated protein kinase catalytic subunit) is an important but not exclusive target of KU-0060648. DNA-PKcs knockdown or dominant negative mutation inhibited HCC cell proliferation. On the other hand, overexpression of wild-type DNA-PKcs enhanced HepG2 cell proliferation. Importantly, KU-0060648 was still cytotoxic to DNA-PKcs-silenced or -mutated HepG2 cells, although its activity in these cells was relatively weak. Further studies showed that KU-0060648 inhibited PI3K-AKT-mTOR activation, independent of DNA-PKcs. Introduction of constitutively-active AKT1 (CA-AKT1) restored AKT-mTOR activation after KU-0060648 treatment in HepG2 cells, and alleviated subsequent cytotoxicity. In vivo, intraperitoneal (i.p.) injection of KU-0060648 significantly inhibited HepG2 xenograft growth in nude mice. AKT-mTOR activation was also inhibited in xenografted tumors. Finally, we showed that DNA-PKcs expression was significantly upregulated in human HCC tissues. Yet miRNA-101, an anti-DNA-PKcs miRNA, was downregulated. Over-expression of miR-101 in HepG2 cells inhibited DNA-PKcs expression and cell proliferation. Together, these results indicate that KU-0060648 inhibits HCC cells through DNA-PKcs-dependent and -independent mechanisms.
基金：
This work is supported by the National Natural Science Foundation (81472786, 81472305 and 81171712), The Six Talents Peak Project of Jiangsu Province (WSN- 012,2014-WSW-061), Kunshan Science and Technology Program (KS1418).
第一作者机构：[1]Department of Oncology, Kunshan First People’s Hospital Affiliated to Jiangsu University, Kunshan 215300, China
共同第一作者：
通讯作者：
通讯机构：[2]Department of Orthopedics, the Second Affiliated Hospital of Soochow University, Suzhou 215000, China[5]Department of Medical Oncology, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi 214023, China[6]Department of Neurosurgery, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
推荐引用方式(GB/T 7714)：
Min-Bin Chen,Zhen-Tao Zhou,Lan Yang,et al.KU-0060648 inhibits hepatocellular carcinoma cells through DNA-PKcs-dependent and DNA-PKcs-independent mechanisms[J].ONCOTARGET.2016,7(13):17047-59.doi:10.18632/oncotarget.7742.
APA：
Min-Bin Chen,Zhen-Tao Zhou,Lan Yang,Mu-Xin Wei,Min Tang...&Pei-Hua Lu.(2016).KU-0060648 inhibits hepatocellular carcinoma cells through DNA-PKcs-dependent and DNA-PKcs-independent mechanisms.ONCOTARGET,7,(13)
MLA：
Min-Bin Chen,et al."KU-0060648 inhibits hepatocellular carcinoma cells through DNA-PKcs-dependent and DNA-PKcs-independent mechanisms".ONCOTARGET 7..13(2016):17047-59
医学