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).
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Apoptosis / genetics
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Carcinoma, Hepatocellular / genetics*
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Carcinoma, Hepatocellular / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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DNA-Activated Protein Kinase / genetics*
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DNA-Activated Protein Kinase / metabolism
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Disease Models, Animal
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Drug Resistance, Neoplasm / genetics*
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Female
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Forkhead Box Protein O3 / metabolism
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Gene Expression
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Heterocyclic Compounds, 4 or More Rings / pharmacology*
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Humans
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Imidazoles
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Liver Neoplasms / genetics*
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Liver Neoplasms / metabolism
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Mice
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Nuclear Proteins / genetics*
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Nuclear Proteins / metabolism
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Protein Transport
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Pyridines
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Pyrimidines
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Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics
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Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
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TNF-Related Apoptosis-Inducing Ligand / genetics
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TNF-Related Apoptosis-Inducing Ligand / metabolism
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Forkhead Box Protein O3
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Heterocyclic Compounds, 4 or More Rings
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Imidazoles
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Nuclear Proteins
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Pyridines
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Pyrimidines
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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TNF-Related Apoptosis-Inducing Ligand
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TNFRSF10B protein, human
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TIC10 compound
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DNA-Activated Protein Kinase
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PRKDC protein, human