Loss of PDCD4 contributes to enhanced chemoresistance in Glioblastoma Multiforme through de-repression of Bcl-xL translation
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Urszula Liwak1,2, Lindsay E. Jordan1,2, Sally Davidson Von-Holt3, Poonam Singh3, Jennifer E.L. Hanson4, Ian A. Lorimer2,4, Federico Roncaroli3, and Martin Holcik1,2,5
1 Apoptosis Research Centre, Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Canada,
2 Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada
3 “John Fulcher” Neuro-oncology Lab, Imperial College, London, UK
4 Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Canada
5 Department of Pediatrics, University of Ottawa, Ottawa, Canada
Martin Holcik, email:
Keywords: Glioblastoma multiforme, Bcl-xL, PDCD4, ABT-737, translation initiation, IRES
Received: July 2, 2013 Accepted: July 26, 2013 Published: July 28, 2013
Glioblastoma multiforme (GBM) is the most common and aggressive form of tumor of the central nervous system. Despite significant efforts to improve treatments, patient survival rarely exceeds 18 months largely due to the highly chemoresistant nature of these tumors. Importantly, misregulation of the apoptotic machinery plays a key role in the development of drug resistance. We previously demonstrated that Bcl-xL, an important anti-apoptotic protein, is regulated at the level of translation by the tumor suppressor programmed cell death 4 (PDCD4). We report here a strong correlation between low expression of PDCD4 and high expression of Bcl-xL in adult de novo GBM, GBM tumor initiating cells, and established GBM cell lines. Importantly, high Bcl-xL expression correlated significantly with poor progression and patient survival. We demonstrate that re-expression of PDCD4 in GBM cells down-regulated Bcl-xL expression and decreased cell viability. Finally, we show that direct inhibition of Bcl-xL by small molecule antagonist ABT-737 sensitizes GBM cells to doxorubicin. Our results identify Bcl-xL as a novel marker of GBM chemoresistance and advocate for the combined use of Bcl-xL antagonists and existing chemotherapeutics as a treatment option for this aggressive tumor.
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