Abstract
Dysregulation of inhibitor of apoptosis (IAP) proteins (IAPs) in hepatocellular carcinoma (HCC) is often associated with poor prognosis. Here we showed that AT406, an IAP antagonist, was cytotoxic and pro-apoptotic to both established (HepG2, SMMC-7721 lines) and primary HCC cells. Activation of mTOR could be a key resistance factor of AT406 in HCC cells. mTOR inhibition (by OSI-027), kinase-dead mutation or knockdown remarkably enhanced AT406-induced lethality in HCC cells. Reversely, forced-activation of mTOR by adding SC79 or exogenous expressing a constitutively active S6K1 (T389E) attenuated AT406-induced cytotoxicity against HCC cells. We showed that AT406 induced degradation of IAPs (cIAP-1 and XIAP), but didn't affect another anti-apoptosis protein Mcl-1. Co-treatment of OSI-027 caused simultaneous Mcl-1 downregulation to overcome AT406's resistance. Significantly, shRNA knockdown of Mcl-1 remarkably facilitated AT406-induced apoptosis in HCC cells. In vivo, AT406 oral administration suppressed HepG2 tumor growth in nude mice. Its activity was potentiated with co-administration of OSI-027. We conclude that mTOR could be a key resistance factor of AT406 in HCC cells.
Keywords:
AT406; Mcl-1; OSI-027; inhibitor of apoptosis (IAP) proteins; mTOR.
MeSH terms
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Acetates / pharmacology
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Animals
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Antineoplastic Agents / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Apoptosis / drug effects*
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Azocines / pharmacology*
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Benzhydryl Compounds / pharmacology*
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Benzopyrans / pharmacology
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Carcinoma, Hepatocellular / drug therapy*
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Carcinoma, Hepatocellular / enzymology
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / pathology
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Dose-Response Relationship, Drug
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Drug Resistance, Neoplasm* / drug effects
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Female
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Hep G2 Cells
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Humans
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Imidazoles / pharmacology
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Inhibitor of Apoptosis Proteins / antagonists & inhibitors*
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Inhibitor of Apoptosis Proteins / metabolism
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Liver Neoplasms / drug therapy*
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Liver Neoplasms / enzymology
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Liver Neoplasms / genetics
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Liver Neoplasms / pathology
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Mice, Nude
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Mutation
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Myeloid Cell Leukemia Sequence 1 Protein / genetics
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Myeloid Cell Leukemia Sequence 1 Protein / metabolism
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Protein Kinase Inhibitors / pharmacology
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Protein Stability
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Proteolysis
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RNA Interference
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Ribosomal Protein S6 Kinases, 70-kDa / genetics
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism
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Signal Transduction / drug effects
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism*
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Time Factors
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Transfection
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Triazines / pharmacology
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Tumor Burden / drug effects
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Ubiquitin-Protein Ligases / antagonists & inhibitors
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Ubiquitin-Protein Ligases / metabolism
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X-Linked Inhibitor of Apoptosis Protein / antagonists & inhibitors
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X-Linked Inhibitor of Apoptosis Protein / metabolism
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Xenograft Model Antitumor Assays
Substances
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AKT activator SC79
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Acetates
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Antineoplastic Agents
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Azocines
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Benzhydryl Compounds
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Benzopyrans
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Imidazoles
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Inhibitor of Apoptosis Proteins
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MCL1 protein, human
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Myeloid Cell Leukemia Sequence 1 Protein
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N-benzhydryl-5-(2-(methylamino)propanamido)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo(1,2-a)(1,5)diazocine-8-carboxamide
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OSI 027
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Protein Kinase Inhibitors
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Triazines
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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BIRC2 protein, human
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Ubiquitin-Protein Ligases
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MTOR protein, human
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Ribosomal Protein S6 Kinases, 70-kDa
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TOR Serine-Threonine Kinases
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ribosomal protein S6 kinase, 70kD, polypeptide 1