Oncotarget

Research Papers:

Identification of DNA-PKcs as a primary resistance factor of TIC10 in hepatocellular carcinoma cells

Long Cheng, Yuan-yuan Liu, Pei-Hua Lu, Yi Peng, Qiang Yuan, Xin-shi Gu, Yong Jin, Min-Bin Chen and Xu-ming Bai _

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Oncotarget. 2017; 8:28385-28394. https://doi.org/10.18632/oncotarget.16073

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Abstract

Long Cheng1,*, Yuan-yuan Liu2,*, Pei-Hua Lu3,*, Yi Peng4, Qiang Yuan1, Xin-shi Gu1, Yong Jin1, Min-Bin Chen2, Xu-ming Bai1

1Department of Interventional Radiology, the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, China

2Department of Oncology, Kunshan First People’s Hospital Affiliated to Jiangsu University, Kunshan, China

3Department of Medical Oncology, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi, China

4Department of Radiotherapy, Hubei Cancer Hospital, Wuhan, China

*These authors contributed equally

Correspondence to:

Min-Bin Chen, email: cmb1981@163.com

Yong Jin, email: jongjinmd@163.com

Xu-ming Bai, email: xumingbaisuda@163.com

Keywords: hepatocellular carcinoma (HCC), TIC10, DNA-PKcs, TRAIL and chemosensitization

Received: February 02, 2017     Accepted: February 27, 2017     Published: March 10, 2017

ABSTRACT

The current study tested the anti-hepatocellular carcinoma (HCC) cell activity of TIC10, a first-in-class small-molecule tumor necrosis (TNF)-related apoptosis-inducing ligand (TRAIL) inducer. TIC10 exerted potent anti-proliferative and pro-apoptotic actions in primary and established human HCC cells. TIC10 blocked Akt-Erk activation, leading to Foxo3a nuclear translocation, as well as TRAIL and death receptor-5 (DR5) transcription in HCC cells. We propose that DNA-PKcs is a major resistance factor of TIC10 possibly via inhibiting Foxo3a nuclear translocation. DNA-PKcs inhibition, knockdown or mutation facilitated TIC10-induced Foxo3a nuclear translocation, TRAIL/DR5 expression and cell apoptosis. Reversely, exogenous DNA-PKcs over-expression inhibited above actions by TIC10. In vivo, oral administration of TIC10 significantly inhibited HepG2 tumor growth in nude mice, which was further potentiated with Nu7026 co-administration. Thus, TIC10 shows promising anti-HCC activity, alone or together with DNA-PKcs inhibitors.


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