title: eIF4E activation is commonly elevated in advanced human prostate cancers and significantly related to reduced patient survival.
abstract: Elevated eukaryotic translation initiation factor 4E (eIF4E) function induces malignancy in experimental models by selectively enhancing translation of key malignancy-related mRNAs (c-myc and BCL-2). eIF4E activation may reflect increased eIF4E expression or phosphorylation of its inhibitory binding proteins (4E-BP). By immunohistochemical analyses of 148 tissues from 89 prostate cancer patients, we now show that both eIF4E expression and 4E-BP1 phosphorylation (p4E-BP1) are increased significantly, particularly in advanced prostate cancer versus benign prostatic hyperplasia tissues. Further, increased eIF4E and p4E-BP1 levels are significantly related to reduced patient survival, whereas uniform 4E-BP1 expression is significantly related to better patient survival. Both immunohistochemistry and Western blotting reveal that elevated eIF4E and p4E-BP1 are evident in the same prostate cancer tissues. In two distinct prostate cancer cell models, the progression to androgen independence also involves increased eIF4E activation. In these prostate cancer cells, reducing eIF4E expression with an eIF4E-specific antisense oligonucleotide currently in phase I clinical trials robustly induces apoptosis, regardless of cell cycle phase, and reduces expression of the eIF4E-regulated proteins BCL-2 and c-myc. Collectively, these data implicate eIF4E activation in prostate cancer and suggest that targeting eIF4E may be attractive for prostate cancer therapy.
authors.affiliation: Lilly Research Labs, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. Graff_jeremy@lilly.com
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Graff
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Konicek
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Lynch
authors.forename: Chad A
authors.initials: CA
authors.lastname: Dumstorf
authors.forename: Michele S
authors.initials: MS
authors.lastname: Dowless
authors.forename: Ann M
authors.initials: AM
authors.lastname: McNulty
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Parsons
authors.forename: Leslie H
authors.initials: LH
authors.lastname: Brail
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Colligan
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Koop
authors.forename: Bernadette M
authors.initials: BM
authors.lastname: Hurst
authors.forename: James A
authors.initials: JA
authors.lastname: Deddens
authors.forename: Blake L
authors.initials: BL
authors.lastname: Neubauer
authors.forename: Louis F
authors.initials: LF
authors.lastname: Stancato
authors.forename: Harry W
authors.initials: HW
authors.lastname: Carter
authors.forename: Larry E
authors.initials: LE
authors.lastname: Douglass
authors.forename: Julia H
authors.initials: JH
authors.lastname: Carter
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D018450:Disease Progression; D039561:Eukaryotic Initiation Factor-4E / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D016376:Oligonucleotides, Antisense / Q000235:genetics; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D039561:Eukaryotic Initiation Factor-4E; C489427:MYC protein, human; D016376:Oligonucleotides, Antisense; D010750:Phosphoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc