| First Author | Ayrault O | Year | 2009 |
| Journal | Proc Natl Acad Sci U S A | Volume | 106 |
| Issue | 40 | Pages | 17037-42 |
| PubMed ID | 19805107 | Mgi Jnum | J:153693 |
| Mgi Id | MGI:4366115 | Doi | 10.1073/pnas.0902880106 |
| Citation | Ayrault O, et al. (2009) Inhibition of Hsp90 via 17-DMAG induces apoptosis in a p53-dependent manner to prevent medulloblastoma. Proc Natl Acad Sci U S A 106(40):17037-42 |
| abstractText | 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. |
