Inhibition of Hsp90 via 17-DMAG induces apoptosis in a p53-dependent manner to prevent medulloblastoma.
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.
Ayrault
Olivier
O
Department of Genetics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
Godeny
Michael D
MD
Dillon
Christopher
C
Zindy
Frederique
F
Fitzgerald
Patrick
P
Roussel
Martine F
MF
Beere
Helen M
HM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D016227:Benzoquinones / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008527:Medulloblastoma / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D016227:Benzoquinones; C493972:Cdkn2c protein, mouse; D018797:Cell Cycle Proteins; D050763:Cyclin-Dependent Kinase Inhibitor p18; D004268:DNA-Binding Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C000606236:PTCH1 protein, human; C488588:PUMA protein, mouse; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases