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KU-0060648 Inhibits Hepatocellular Carcinoma Cells Through DNA-PKcs-dependent and DNA-PKcs-independent Mechanisms

KU-0060648 Inhibits Hepatocellular Carcinoma Cells Through DNA-PKcs-dependent and DNA-PKcs-independent Mechanisms

Min-Bin Chen, Zhen-Tao Zhou, Lan Yang, Mu-Xin Wei, Min Tang, Ting-Yan Ruan, Jun-Ying Xu, Xiao-Zhong Zhou, Gang Chen, Pei-Hua Lu

Oncotarget. 2016 Mar 29;7(13):17047-59.

PMID: 26933997

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP881375004	KU-0060648		881375-00-4	Price

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