Identification of DNA-PKcs as a primary resistance factor of TIC10 in hepatocellular carcinoma cells
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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
Min-Bin Chen, email: firstname.lastname@example.org
Yong Jin, email: email@example.com
Xu-ming Bai, email: firstname.lastname@example.org
Keywords: hepatocellular carcinoma (HCC), TIC10, DNA-PKcs, TRAIL and chemosensitization
Received: February 02, 2017 Accepted: February 27, 2017 Published: March 10, 2017
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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