Abstract
Inhibitory regulators of apoptosis play a critical role in the responsiveness of tumour cells to cytotoxic agents. The X-linked inhibitor of apoptosis protein (XIAP) is a member of a novel family of Inhibitor of Apoptosis (IAP) proteins. Here we show that acute low dose ionizing irradiation results in the translational upregulation of XIAP that correlates with an increased resistance to radiation in non-small cell lung carcinoma. This upregulation is mediated by an internal ribosome binding mechanism via an IRES element located within a XIAP 5′ UTR. Transient overexpression of XIAP rendered human carcinoma cells resistant to low dose γ-irradiation. By contrast, the antisense targeting of XIAP resulted in increased cell death following irradiation advocating a distinct role for XIAP in radiation resistant phenotype of human cancers.
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Acknowledgements
We thank P Liston for the gift of adenoviral vectors, C Neville for sequencing and members of our laboratories for critical discussions. This work was supported in part by grants from the Medical Research Council of Canada (MRC), the Canadian Networks of Centers of Excellence (NCE), National Cancer Institute of Canada, Cancer Research Society, the Howard Hughes Medical Institute (HHMI), and the Apoptogen Inc. M Holcik is a recipient of a MRC Postdoctoral Fellowship. RG Korneluk is a recipient of a MRC Senior Scientist Award, A Fellow of the Royal Society of Canada, and a HHMI International Research Scholar.
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Holcik, M., Yeh, C., Korneluk, R. et al. Translational upregulation of X-linked inhibitor of apoptosis (XIAP) increases resistance to radiation induced cell death. Oncogene 19, 4174–4177 (2000). https://doi.org/10.1038/sj.onc.1203765
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DOI: https://doi.org/10.1038/sj.onc.1203765
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