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Oncotarget. 2017 Apr 25;8(17):28385-28394. doi: 10.18632/oncotarget.16073.

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

Author information

1
Department of Interventional Radiology, the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, China.
2
Department of Oncology, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, China.
3
Department of Medical Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China.
4
Department of Radiotherapy, Hubei Cancer Hospital, Wuhan, China.

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.

KEYWORDS:

DNA-PKcs; TIC10; TRAIL and chemosensitization; hepatocellular carcinoma (HCC)

PMID:
28415690
PMCID:
PMC5438657
DOI:
10.18632/oncotarget.16073
[Indexed for MEDLINE]
Free PMC Article

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