Abstract:
:P53 wild-type and p53-null or mutant cells undergo a G(2)-phase cell-cycle arrest in response to ionizing radiation (IR). In this study we examined the effect of heat-shock protein 90 (HSP90) inhibitor, geldanamycin (GA), on IR-induced G(2) arrest in human colon adenocarcinoma cells with different p53 status. We show that GA treatment abrogates IR-induced G(2)-phase arrest in cells null or mutant for p53. Specifically, GA treatment pushed irradiated p53 signaling-defective cells into a premature mitosis characterized by aberrant mitotic figures, increased gammaH2AX expression and formation of micronucleated cells. Cells expressing wild-type p53 were resistant to GA-induced G(2) checkpoint abrogation. Notably, GA treatment decreased levels of G(2) regulatory proteins Wee1 and Chk1, and inhibitory phosphorylation of Cdc2, independent of p53 status. Further investigation identified p21 as the potential downstream effector of p53 that mediates resistance to G(2) checkpoint abrogation. Clonogenic survival studies demonstrated higher sensitivity to GA alone or combination IR plus GA treatment in p53 and p21-null cells. Collectively, these data demonstrate potential mechanisms through which HSP90 inhibition can enhance the effects of ionizing radiation in p53-compromised cancer cells. Combination IR plus HSP90 inhibitor therapies may be particularly useful in treating cancers that lack wild-type p53.
journal_name
Oncogenejournal_title
Oncogeneauthors
Moran DM,Gawlak G,Jayaprakash MS,Mayar S,Maki CGdoi
10.1038/onc.2008.172subject
Has Abstractpub_date
2008-09-18 00:00:00pages
5567-77issue
42eissn
0950-9232issn
1476-5594pii
onc2008172journal_volume
27pub_type
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