title: Loss of PDCD4 contributes to enhanced chemoresistance in Glioblastoma multiforme through de-repression of Bcl-xL translation.
abstract: 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.
authors: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada.
authors: Urszula
authors: U
authors: Liwak
authors: Lindsay E
authors: LE
authors: Jordan
authors: Sally Davidson
authors: SD
authors: Von-Holt
authors: Poonam
authors: P
authors: Singh
authors: Jennifer E L
authors: JE
authors: Hanson
authors: Ian A
authors: IA
authors: Lorimer
authors: Federico
authors: F
authors: Roncaroli
authors: Martin
authors: M
authors: Holcik
mesh_terms: D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009596:Nitrophenols / Q000008:administration & dosage / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D014176:Protein Biosynthesis; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C501332:ABT-737; D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; D001713:Biphenyl Compounds; D009596:Nitrophenols; C114487:PDCD4 protein, human; D010879:Piperazines; D016601:RNA-Binding Proteins; D013449:Sulfonamides; D051020:bcl-X Protein; D004317:Doxorubicin
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