mTOR/4E‐BP1 Pathway is a Translational Regulator of Prostate Cancer Progression

• Published in: The FASEB journal 2006-03, Vol.20 (4), p.A109-A109
• Main Authors: Karpisheva, Ksenia V, Xi, Qiaoran, Braunstein, Steve, Melamed, Jonathan, Goldberg, Judith, Schneider, Robert
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.20.4.A109-c

We identified and tested the changes in the translation apparatus that characterized the molecular and biochemical changes in the translational machinery associated with development and progression of prostate cancer. Immunohistochemical staining of tumor tissue arrays contained 100 cases of prostrate cancer and correspondent normal tissue revealed the major key translational alteration, strong over‐expression of 4E‐BP1 compared to normal prostate epithelium. Strikingly, expression of 4E‐BP1 was lost with progression of tumors from Gleason grade 6 to Gleason grade 9. FISH analysis of 4E‐BP1 demonstrated 3–5 fold gene amplification in prostate cancers of Gleason grade 6 but rearrangement or loss with Gleason 8–10. These changes were confirmed at the mRNA level by qRT‐PCR. Overexpression of 4–5 fold 4E‐BP1 in the prostate DU145 cell line increased tumor growth potential in Chick Embryo Choriallantonic Membrane (CAM) assays by more then 30%. Expression of 4E‐BP1 mutants that cannot eIF4E showed the importance of eIF4E‐4E‐BP1 interaction for this effect. Biochemical analysis of the corresponding tumors by immunoblot analysis showed activation of the Akt/mTOR pathway in the tumors that overexpressed 4E‐BP1. Analysis of primary prostate tumors by immunoblot showed activation of the Akt/mTOR pathway in 4E‐BP1 overexpressing tumors as well. These and other studies demonstrate that the 4E‐BP1 gene is amplified in most prostate tumors of low metastatic potential and lost in tumors with high metastatic potential, promoting translation adaptation and resulting in greater tumor growth