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.
Highlights
The prognosis and five-year survival of hepatocellular carcinoma (HCC) patients are often poor, yet the incidence is rising [1, 2]
We propose that DNA-PKcs is a major resistance factor of TIC10 possibly via inhibiting Foxo3a nuclear translocation
We propose that DNA-PKcs could be a primary resistant factor of TIC10 in HCC cells
Summary
The prognosis and five-year survival of hepatocellular carcinoma (HCC) patients are often poor, yet the incidence is rising [1, 2]. Preclinical studies have demonstrated that TIC10 could be a novel and promising anti-cancer agent, which efficiently kills various cancer cells [10, 13,14,15,16,17,18]. TIC10 blocks Akt and Erk signalings, leading to Foxo3a nuclear translocation, which dictates TRAIL and death receptor-5 (DR5) transcription [11, 12, 19]. This would eventually activate TRAIL-mediated apoptosis pathway to kill cancer cells [11, 12, 19]. The potential effect and possible underlying mechanisms of TIC10 against human HCC cells were studied
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