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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.

Titel:	Inhibition of Hsp90 via 17-DMAG induces apoptosis in a p53-dependent manner to prevent medulloblastoma.
Autor/in / Beteiligte Person:	Ayrault, O ; Godeny, MD ; Dillon, C ; Zindy, F ; Fitzgerald, P ; Roussel, MF ; Beere, HM
Link:	Full Text Finder (Volltext)
Zeitschrift:	Proceedings of the National Academy of Sciences of the United States of America, Jg. 106 (2009-10-06), Heft 40, S. 17037-42
Veröffentlichung:	Washington, DC : National Academy of Sciences, 2009
Medientyp:	academicJournal
ISSN:	1091-6490 (electronic)
DOI:	10.1073/pnas.0902880106
Schlagwort:	Animals Apoptosis Regulatory Proteins genetics Apoptosis Regulatory Proteins metabolism Ataxia Telangiectasia Mutated Proteins Cell Cycle drug effects Cell Cycle Proteins genetics Cell Cycle Proteins metabolism Cell Line, Tumor Cells, Cultured Cyclin-Dependent Kinase Inhibitor p18 genetics Cyclin-Dependent Kinase Inhibitor p18 metabolism DNA-Binding Proteins genetics DNA-Binding Proteins metabolism Fibroblasts cytology Fibroblasts drug effects Fibroblasts metabolism Flow Cytometry HSP90 Heat-Shock Proteins antagonists & inhibitors HSP90 Heat-Shock Proteins genetics Humans Immunoblotting Immunohistochemistry Medulloblastoma genetics Medulloblastoma pathology Mice Mice, Knockout Mice, Nude Neoplasms, Experimental genetics Neoplasms, Experimental pathology Neoplasms, Experimental prevention & control Patched Receptors Patched-1 Receptor Protein Serine-Threonine Kinases genetics Protein Serine-Threonine Kinases metabolism Receptors, Cell Surface genetics Receptors, Cell Surface metabolism Reverse Transcriptase Polymerase Chain Reaction Tumor Cells, Cultured Tumor Suppressor Protein p53 genetics Tumor Suppressor Proteins genetics Tumor Suppressor Proteins metabolism Apoptosis drug effects Benzoquinones pharmacology HSP90 Heat-Shock Proteins metabolism Lactams, Macrocyclic pharmacology Medulloblastoma prevention & control Tumor Suppressor Protein p53 metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Language: English [Proc Natl Acad Sci U S A] 2009 Oct 06; Vol. 106 (40), pp. 17037-42. <i>Date of Electronic Publication: </i>2009 Sep 23. MeSH Terms: Apoptosis / drug effects ; Benzoquinones / pharmacology ; HSP90 Heat-Shock Proteins / metabolism ; Lactams, Macrocyclic / pharmacology ; Medulloblastoma / prevention & control ; Tumor Suppressor Protein p53 / metabolism ; Animals ; Apoptosis Regulatory Proteins / genetics ; Apoptosis Regulatory Proteins / metabolism ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle / drug effects ; Cell Cycle Proteins / genetics ; Cell Cycle Proteins / metabolism ; Cell Line, Tumor ; Cells, Cultured ; Cyclin-Dependent Kinase Inhibitor p18 / genetics ; Cyclin-Dependent Kinase Inhibitor p18 / metabolism ; DNA-Binding Proteins / genetics ; DNA-Binding Proteins / metabolism ; Fibroblasts / cytology ; Fibroblasts / drug effects ; Fibroblasts / metabolism ; Flow Cytometry ; HSP90 Heat-Shock Proteins / antagonists & inhibitors ; HSP90 Heat-Shock Proteins / genetics ; Humans ; Immunoblotting ; Immunohistochemistry ; Medulloblastoma / genetics ; Medulloblastoma / pathology ; Mice ; Mice, Knockout ; Mice, Nude ; Neoplasms, Experimental / genetics ; Neoplasms, Experimental / pathology ; Neoplasms, Experimental / prevention & control ; Patched Receptors ; Patched-1 Receptor ; Protein Serine-Threonine Kinases / genetics ; Protein Serine-Threonine Kinases / metabolism ; Receptors, Cell Surface / genetics ; Receptors, Cell Surface / metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53 / genetics ; Tumor Suppressor Proteins / genetics ; Tumor Suppressor Proteins / metabolism References: Nat Rev Cancer. 2005 Oct;5(10):761-72. 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(PMID: 11507088) Grant Information: P01 CA096832 United States CA NCI NIH HHS; P30 CA021765 United States CA NCI NIH HHS; CA-096832-10 United States CA NCI NIH HHS; 5P30CA021765-29 United States CA NCI NIH HHS Substance Nomenclature: 0 (Apoptosis Regulatory Proteins) ; 0 (Benzoquinones) ; 0 (Cdkn2c protein, mouse) ; 0 (Cell Cycle Proteins) ; 0 (Cyclin-Dependent Kinase Inhibitor p18) ; 0 (DNA-Binding Proteins) ; 0 (HSP90 Heat-Shock Proteins) ; 0 (Lactams, Macrocyclic) ; 0 (PTCH1 protein, human) ; 0 (PUMA protein, mouse) ; 0 (Patched Receptors) ; 0 (Patched-1 Receptor) ; 0 (Ptch1 protein, mouse) ; 0 (Receptors, Cell Surface) ; 0 (Tumor Suppressor Protein p53) ; 0 (Tumor Suppressor Proteins) ; 001L2FE0M3 (17-(dimethylaminoethylamino)-17-demethoxygeldanamycin) ; EC 2.7.11.1 (ATM protein, human) ; EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins) ; EC 2.7.11.1 (Atm protein, mouse) ; EC 2.7.11.1 (Protein Serine-Threonine Kinases) Entry Date(s): Date Created: 20091007 Date Completed: 20100115 Latest Revision: 20211203 Update Code: 20240513 PubMed Central ID: PMC2761355

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Inhibition of Hsp90 via 17-DMAG induces apoptosis in a p53-dependent manner to prevent medulloblastoma.