Abstract
NF-κB and Akt are two main cell survival pathways that attenuate the anticancer efficacy of therapeutics. Our previous studies demonstrated that the Smac mimetic compound 3 (SMC3) specifically suppresses c-IAP1 and induces TNF-α autocrine to kill cancer cells. However, SMC3 also induces a cell survival signal through NF-κB activation. In this report, we further found that SMC3 potently activates Akt, which inhibits SMC3-induced cancer cell death. Strikingly, concurrent blocking NF-κB and Akt resulted in a significantly potentiated cytotoxicity. Because heat shock protein 90 (Hsp90) plays an important role in maintaining the integrity of both the NF-κB and Akt pathways in cancer cells, we examined if suppression of Hsp90 is able to potentiate SMC3-induced cancer cell death. The results show that targeting Hsp90 does not interfere with SMC3-induced c-IAP1 degradation and TNF-α autocrine, the key processes for SMC3-induced cancer cell apoptosis. However, Hsp90 inhibitors effectively blocked SMC3-induced NF-κB activation through degradation of RIP1 and IKKβ, two key components of the NF-κB activation pathway, and reduced both the constitutive and SMC3-induced Akt activity through degradation of the Akt protein. Consistently, with the co-treatment of SMC3 and Hsp90 inhibitors, apoptosis was markedly sensitized and a synergistic cytotoxicity was observed. The results suggest that concurrent targeting c-IAP1 and Hsp90 by combination of SMC3 and Hsp90 inhibitors is an effective approach for improving the anticancer value of SMC3.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Apoptosis / drug effects
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Apoptosis Regulatory Proteins
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Blotting, Western
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Cell Line, Tumor
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Cell Survival / drug effects
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Drug Synergism
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Gene Expression
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HSP90 Heat-Shock Proteins / antagonists & inhibitors*
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HSP90 Heat-Shock Proteins / metabolism
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Heterocyclic Compounds, 2-Ring / pharmacology*
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Humans
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I-kappa B Kinase / antagonists & inhibitors*
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I-kappa B Kinase / genetics
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I-kappa B Kinase / metabolism
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Intracellular Signaling Peptides and Proteins / pharmacology*
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Liver Neoplasms / metabolism
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Lung Neoplasms / metabolism
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism
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Mitochondrial Proteins / pharmacology*
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NF-kappa B / antagonists & inhibitors*
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NF-kappa B / metabolism
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
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Proto-Oncogene Proteins c-akt / metabolism
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Pyrazoles / pharmacology*
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Rifabutin / pharmacology*
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Signal Transduction / drug effects
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Tumor Necrosis Factor-alpha / metabolism
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X-Linked Inhibitor of Apoptosis Protein / antagonists & inhibitors*
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X-Linked Inhibitor of Apoptosis Protein / metabolism
Substances
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Apoptosis Regulatory Proteins
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CCT018159
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DIABLO protein, human
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HSP90 Heat-Shock Proteins
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Heterocyclic Compounds, 2-Ring
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Intracellular Signaling Peptides and Proteins
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Mitochondrial Proteins
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NF-kappa B
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Pyrazoles
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Tumor Necrosis Factor-alpha
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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Rifabutin
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Proto-Oncogene Proteins c-akt
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I-kappa B Kinase