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Geldanamycin promotes premature mitotic entry and micronucleation in irradiated p53/p21 deficient colon carcinoma cells

Oncogene volume 27, pages 5567–5577 (2008)Cite this article

Abstract

P53 wild-type and p53-null or mutant cells undergo a G2-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 G2 arrest in human colon adenocarcinoma cells with different p53 status. We show that GA treatment abrogates IR-induced G2-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 γH2AX expression and formation of micronucleated cells. Cells expressing wild-type p53 were resistant to GA-induced G2 checkpoint abrogation. Notably, GA treatment decreased levels of G2 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 G2 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.

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Acknowledgements

This work was supported by National Institutes of Health Grant RO1 CA080918.

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Authors and Affiliations

  1. Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USA

    D M Moran, G Gawlak, M S Jayaprakash, S Mayar & C G Maki

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  1. D M Moran
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  2. G Gawlak
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  3. M S Jayaprakash
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  5. C G Maki
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Correspondence to C G Maki.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Moran, D., Gawlak, G., Jayaprakash, M. et al. Geldanamycin promotes premature mitotic entry and micronucleation in irradiated p53/p21 deficient colon carcinoma cells. Oncogene 27, 5567–5577 (2008). https://doi.org/10.1038/onc.2008.172

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