17-(dimethylaminoethylamino)-17-demethoxygeldanamycin and 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.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Ataxia Telangiectasia Mutated Proteins; Benzoquinones; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p18; DNA-Binding Proteins; Fibroblasts; Flow Cytometry; HSP90 Heat-Shock Proteins; Humans; Immunoblotting; Immunohistochemistry; Lactams, Macrocyclic; Medulloblastoma; Mice; Mice, Knockout; Mice, Nude; Neoplasms, Experimental; Patched Receptors; Patched-1 Receptor; Protein Serine-Threonine Kinases; Receptors, Cell Surface; Reverse Transcriptase Polymerase Chain Reaction; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Tumor Suppressor Proteins