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Survivin enhances radiation resistance in primary human glioblastoma cells



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Oncogene 2004 23 7494 7506 2004 Nature Publishing Group All rights reserved 0950 9232 04 30 00 www nature com onc Survivin enhances radiation resistance in primary human glioblastoma cells via caspase independent mechanisms Arnab Chakravarti 1 Gary G Zhai1 Min Zhang1 Rajeev Malhotra1 Douglas E Latham1 Meaghan A Delaney1 Pierre Robe2 Ulf Nestler3 Qinhui Song1 and Jay Loef er1 1 Department of Radiation Oncology Massachusetts General Hospital Harvard Medical School Boston MA USA 2Department of Neurosurgery Brigham and Women s Hospital Harvard Medical School Boston MA USA 3Department of Neurosurgery Justus Liebig University Giessen Germany The observed radioresistance of human glioblastoma multiforme GBM poses a major challenge which if overcome may lead to signi cant advances in the management of this patient population There is accumulating evidence from correlative studies that Survivin expression is associated with increased malignant potential of human gliomas The purpose of this study was to investigate whether Survivin plays a direct role in mediating radiation resistance in primary human glioma cell lines and if so investigating the underlying mechanisms Our panel of GBM cell lines included two that were relatively radiation resistant GM20 and GM21 and two that were more radiation sensitive GM22 and GM23 which demonstrated differential levels of Survivin expression between the two groups Through the use of adenoviral vectors containing either dominant negative pAd S T34A or wild type Suvrivin pAd S WT we were able to inactivate or overexpress Survivin respectively Our ndings suggest that Survivin plays a critical role in mediating radiation resistance in primary GBM cells in part through suppression of apoptotic cell death via a caspase independent manner We have identi ed novel mechanisms by which Survivin may enhance tumor cell survival upon radiation exposure such as regulation of double strand DNA break repair and tumor cell metabolism which were most



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