期刊
ONCOTARGET
卷 4, 期 9, 页码 1365-1372出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.1154
关键词
Glioblastoma multiforme; Bcl-xL; PDCD4; ABT-737; translation initiation; IRES
资金
- Ontario Graduate Scholarship
- Canadian Institute of Health Research
- Cancer Research Society
- Brain Tumor Research Campaign [295895]
- European Union [HEALTH-F2-2011-278850]
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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