Abstract
Elevated expression of HSP90 is observed in many tumor types and is associated with a limited clinical response. Targeting HSP90 using inhibitors such as 17-DMAG (17-desmethoxy-17-N,N-dimethylaminoethylaminogeldanamycin) has shown limited therapeutic success. HSP90 regulates the function of several proteins implicated in tumorigenesis although the precise mechanism through which 17-DMAG regulates tumor cell survival remains unclear. We observed a requirement for p53 in mediating 17-DMAG-induced cell death. The sensitivity of primary mouse embryonic fibroblasts and tumor cells to 17-DMAG-induced apoptosis depended on the p53 status. Wild-type MEFs underwent 17-DMAG-induced caspase-dependent cell death, whilst those lacking p53 failed to do so. Interestingly p53-dependent cell death occurred independently of Atm or Arf. Primary tumor cells derived from two models of murine medulloblastoma (Ptch1(+/-);Ink4c(-/-) and p53(FL/FL);Nestin-Cre(+); Ink4c(-/-)) that retain and lack p53 function, respectively, displayed a dependence on functional p53 to engage 17-DMAG-induced apoptosis. Strikingly, 17-DMAG treatment in an allograft model of Ptch1(+/-);Ink4c(-/-) but not p53(FL/FL);Nestin-Cre(+); Ink4c(-/-) tumor cells prevented tumor growth in vivo. Our data suggest that p53 status is a likely predictor of the sensitivity of tumors to 17-DMAG.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects*
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Ataxia Telangiectasia Mutated Proteins
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Benzoquinones / pharmacology*
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Cell Cycle / drug effects
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Cells, Cultured
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Cyclin-Dependent Kinase Inhibitor p18 / genetics
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Cyclin-Dependent Kinase Inhibitor p18 / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Flow Cytometry
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HSP90 Heat-Shock Proteins / antagonists & inhibitors
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HSP90 Heat-Shock Proteins / genetics
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HSP90 Heat-Shock Proteins / metabolism*
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Humans
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Immunoblotting
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Immunohistochemistry
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Lactams, Macrocyclic / pharmacology*
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Medulloblastoma / genetics
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Medulloblastoma / pathology
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Medulloblastoma / prevention & control*
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Mice
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Mice, Knockout
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Mice, Nude
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Neoplasms, Experimental / genetics
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Neoplasms, Experimental / pathology
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Neoplasms, Experimental / prevention & control
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Patched Receptors
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Patched-1 Receptor
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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Apoptosis Regulatory Proteins
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Benzoquinones
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Cdkn2c protein, mouse
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p18
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DNA-Binding Proteins
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HSP90 Heat-Shock Proteins
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Lactams, Macrocyclic
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PTCH1 protein, human
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PUMA protein, mouse
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Patched Receptors
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Patched-1 Receptor
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Ptch1 protein, mouse
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Receptors, Cell Surface
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Protein Serine-Threonine Kinases