eIF4E activation is commonly elevated in advanced human prostate cancers and significantly related to reduced patient survival.

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.

[1]  J. Burch,et al.  High-content imaging characterization of cell cycle therapeutics through in vitro and in vivo subpopulation analysis , 2008, Molecular Cancer Therapeutics.

[2]  J. Graff,et al.  Targeting the eukaryotic translation initiation factor 4E for cancer therapy. , 2008, Cancer research.

[3]  H. Yee,et al.  A hypoxia-controlled cap-dependent to cap-independent translation switch in breast cancer. , 2007, Molecular cell.

[4]  Tao Wang,et al.  Therapeutic suppression of translation initiation factor eIF4E expression reduces tumor growth without toxicity. , 2007, The Journal of clinical investigation.

[5]  C. Proud Signalling to translation: how signal transduction pathways control the protein synthetic machinery. , 2007, The Biochemical journal.

[6]  N. Sonenberg,et al.  Epigenetic Activation of a Subset of mRNAs by eIF4E Explains Its Effects on Cell Proliferation , 2007, PloS one.

[7]  J. Baselga,et al.  4E-Binding Protein 1, A Cell Signaling Hallmark in Breast Cancer that Correlates with Pathologic Grade and Prognosis , 2007, Clinical Cancer Research.

[8]  K. Borden,et al.  eIF4E is a central node of an RNA regulon that governs cellular proliferation , 2006, The Journal of cell biology.

[9]  J. Baselga,et al.  Phosphorylated 4E binding protein 1: A hallmark of cell signaling that correlates with survival in ovarian cancer , 2006, Cancer.

[10]  Claes Wahlestedt,et al.  Apoptosis resistance downstream of eIF4E: posttranscriptional activation of an anti-apoptotic transcript carrying a consensus hairpin structure , 2006, Nucleic acids research.

[11]  Robert R. Klein,et al.  Expression of mTOR signaling pathway markers in prostate cancer progression , 2006, The Prostate.

[12]  A. De Benedetti,et al.  Reduction of translation initiation factor 4E decreases the malignancy of ras ‐transformed cloned rat embryo fibroblasts , 2006 .

[13]  W. Sellers,et al.  Akt-regulated pathways in prostate cancer , 2005, Oncogene.

[14]  R. Campbell,et al.  The Protein Kinase Cβ–Selective Inhibitor, Enzastaurin (LY317615.HCl), Suppresses Signaling through the AKT Pathway, Induces Apoptosis, and Suppresses Growth of Human Colon Cancer and Glioblastoma Xenografts , 2005 .

[15]  J. Isaacs,et al.  Prostate cancer: potential targets of anti-proliferative and apoptotic signaling pathways. , 2005, The international journal of biochemistry & cell biology.

[16]  N. Sonenberg,et al.  Activation of translation complex eIF4F is essential for the genesis and maintenance of the malignant phenotype in human mammary epithelial cells. , 2004, Cancer cell.

[17]  J. Deddens,et al.  Pak-1 Expression Increases with Progression of Colorectal Carcinomas to Metastasis , 2004, Clinical Cancer Research.

[18]  M. Peterson,et al.  Translation Initiation Factor 4E Blocks Endoplasmic Reticulum-mediated Apoptosis* , 2004, Journal of Biological Chemistry.

[19]  P. Pandolfi,et al.  The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis , 2004, Nature Medicine.

[20]  N. Sonenberg,et al.  eIF4E – from translation to transformation , 2004, Oncogene.

[21]  J. Graff,et al.  eIF-4E expression and its role in malignancies and metastases , 2004, Oncogene.

[22]  S. Lowe,et al.  Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy , 2004, Nature.

[23]  M. Peterson,et al.  Translation Factor eIF4E Rescues Cells from Myc-dependent Apoptosis by Inhibiting Cytochromec Release* , 2003, The Journal of Biological Chemistry.

[24]  F. S. French,et al.  Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. , 2001, Cancer research.

[25]  R. Vessella,et al.  Increased AKT Activity Contributes to Prostate Cancer Progression by Dramatically Accelerating Prostate Tumor Growth and Diminishing p27Kip1 Expression* , 2000, The Journal of Biological Chemistry.

[26]  J. Fando,et al.  4E binding protein 1 expression is inversely correlated to the progression of gastrointestinal cancers. , 2000, The international journal of biochemistry & cell biology.

[27]  A. De Benedetti,et al.  Antisense RNA to eIF4E Suppresses Oncogenic Properties of a Head and Neck Squamous Cell Carcinoma Cell Line , 2000, The Laryngoscope.

[28]  R. Fåhraeus,et al.  Rapid induction of apoptosis mediated by peptides that bind initiation factor eIF4E , 2000, Current Biology.

[29]  S. Zimmer,et al.  Translational control of malignancy: the mRNA cap-binding protein, eIF-4E, as a central regulator of tumor formation, growth, invasion and metastasis. , 2000, Anticancer research.

[30]  E. Fearon,et al.  Cancer progression , 1999, Current Biology.

[31]  T. Visakorpi,et al.  Genetic alterations in hormone-refractory recurrent prostate carcinomas. , 1998, The American journal of pathology.

[32]  A. Gingras,et al.  4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. , 1998, Genes & development.

[33]  Benjamin D. L. Li,et al.  Elevated expression of eIF4E and FGF-2 isoforms during vascularization of breast carcinomas , 1997, Oncogene.

[34]  Christine C. Hudson,et al.  Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. , 1997, Science.

[35]  A. Gingras,et al.  The eIF4E-binding proteins 1 and 2 are negative regulators of cell growth. , 1996, Oncogene.

[36]  N. Sonenberg,et al.  Translational control of programmed cell death: eukaryotic translation initiation factor 4E blocks apoptosis in growth-factor-restricted fibroblasts with physiologically expressed or deregulated Myc , 1996, Molecular and cellular biology.

[37]  Franck Bladou,et al.  Prostatic cell lineage markers: Emergence of BCL2+ cells of human prostate cancer xenograft LuCaP 23 following castration , 1996, International journal of cancer.

[38]  R W Veltri,et al.  Implication of cell kinetic changes during the progression of human prostatic cancer. , 1995, Clinical cancer research : an official journal of the American Association for Cancer Research.

[39]  A. De Benedetti,et al.  Decreasing the level of translation initiation factor 4E with antisense rna causes reversal of ras‐mediated transformation and tumorigenesis of cloned rat embryo fibroblasts , 1993, International journal of cancer.

[40]  D. Chopin,et al.  Detection of the apoptosis-suppressing oncoprotein bc1-2 in hormone-refractory human prostate cancers. , 1993, The American journal of pathology.

[41]  D. Gleason,et al.  Histologic grading of prostate cancer: a perspective. , 1992, Human pathology.

[42]  N. Sonenberg,et al.  Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5' cap , 1990, Nature.

[43]  C. Proud,et al.  Methods for studying signal-dependent regulation of translation factor activity. , 2007, Methods in enzymology.