Abstract
Histone deacetylase 6 (HDAC6) inhibition, recently, has been shown to promote the acetylation of heat-shock protein 90 (Hsp90) and disrupt its chaperone function. Her-2 oncoprotein is identified as a client protein of Hsp90. Therefore, in this study we examined the effect of carbamazepine, which could inhibit HDAC on Hsp90 acetylation and Her-2 stability. The results of this study demonstrate that while carbamazepine had no effect on the Her-2 mRNA level, it induced Her-2 protein degradation via the proteasome pathway by disrupting the chaperone function of Hsp90 in SK-BR-3 cells. Mechanistically, carbamazepine could enhance the acetylation of α-tubulin, indicating its inhibitory effect on HDAC6. Functionally, carbamazepine could synergize with trastuzumab or geldanamycin to promote Her-2 degradation and inhibit breast cancer cell proliferation. Thus, this study has potential clinical implications by providing a promising strategy to overcome the development of resistance against trastuzumab therapy for breast cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Antibodies, Monoclonal / pharmacology
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Benzoquinones
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Breast Neoplasms / enzymology*
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Breast Neoplasms / genetics
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Breast Neoplasms / pathology
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Carbamazepine / pharmacology*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cysteine Proteinase Inhibitors / pharmacology
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Dose-Response Relationship, Drug
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Drug Synergism
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Female
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HSP90 Heat-Shock Proteins / antagonists & inhibitors
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HSP90 Heat-Shock Proteins / metabolism*
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Histone Deacetylase 6
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Histone Deacetylase Inhibitors / pharmacology*
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Histone Deacetylases / metabolism*
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Humans
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Lactams, Macrocyclic
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Leupeptins / pharmacology
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Proteasome Endopeptidase Complex / drug effects
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Proteasome Endopeptidase Complex / metabolism
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Protein Processing, Post-Translational / drug effects*
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Protein Stability
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RNA, Messenger / metabolism
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Receptor, ErbB-2 / genetics
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Receptor, ErbB-2 / metabolism*
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Time Factors
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Trastuzumab
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Tubulin / metabolism
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents
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Benzoquinones
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Cysteine Proteinase Inhibitors
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HSP90 Heat-Shock Proteins
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Histone Deacetylase Inhibitors
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Lactams, Macrocyclic
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Leupeptins
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RNA, Messenger
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Tubulin
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Carbamazepine
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tanespimycin
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ERBB2 protein, human
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Receptor, ErbB-2
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Proteasome Endopeptidase Complex
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HDAC6 protein, human
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Histone Deacetylase 6
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Histone Deacetylases
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Trastuzumab
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde