Abstract
Heat-shock protein 70 (HSP70) isoforms contribute to tumorigenesis through their well-documented antiapoptotic activity and via their role as cochaperones for the HSP90 molecular chaperone. HSP70 expression is induced following treatment with HSP90 inhibitors, which may attenuate the cell death effects of this class of inhibitor. Here we show that silencing either heat-shock cognate 70 (HSC70) or HSP72 expression in human cancer cell lines has no effect on HSP90 activity or cell proliferation. However, simultaneously reducing the expression of both of these isoforms induces proteasome-dependent degradation of HSP90 client proteins, G1 cell-cycle arrest, and extensive tumor-specific apoptosis. Importantly, simultaneous silencing of HSP70 isoforms in nontumorigenic cell lines does not result in comparable growth arrest or induction of apoptosis, indicating a potential therapeutic window.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects
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Apoptosis / physiology*
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Benzoquinones / pharmacology
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Boronic Acids / pharmacology
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Bortezomib
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Cell Cycle / drug effects
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Cell Line
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cyclin-Dependent Kinase 4 / metabolism
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HCT116 Cells
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HSC70 Heat-Shock Proteins / genetics*
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HSC70 Heat-Shock Proteins / metabolism
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HSP70 Heat-Shock Proteins / metabolism
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HSP72 Heat-Shock Proteins / genetics*
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HSP72 Heat-Shock Proteins / metabolism
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HSP90 Heat-Shock Proteins / antagonists & inhibitors
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HSP90 Heat-Shock Proteins / metabolism*
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Humans
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Kinetics
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Lactams, Macrocyclic / pharmacology
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Neoplasms / genetics
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Neoplasms / metabolism
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Neoplasms / pathology
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Poly(ADP-ribose) Polymerases / metabolism
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Protease Inhibitors / pharmacology
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Proteasome Endopeptidase Complex / metabolism
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Proteasome Inhibitors
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Proto-Oncogene Proteins c-raf / metabolism
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Pyrazines / pharmacology
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RNA, Small Interfering / genetics
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Transfection
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Ubiquitination
Substances
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Benzoquinones
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Boronic Acids
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HSC70 Heat-Shock Proteins
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HSP70 Heat-Shock Proteins
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HSP72 Heat-Shock Proteins
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HSP90 Heat-Shock Proteins
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HSPA8 protein, human
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Lactams, Macrocyclic
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Protease Inhibitors
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Proteasome Inhibitors
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Protein Isoforms
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Pyrazines
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RNA, Small Interfering
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mortalin
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tanespimycin
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Bortezomib
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Poly(ADP-ribose) Polymerases
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Proto-Oncogene Proteins c-raf
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CDK4 protein, human
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Cyclin-Dependent Kinase 4
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Proteasome Endopeptidase Complex