title: Elevated Translation Initiation Factor eIF4E Is an Attractive Therapeutic Target in Multiple Myeloma.
abstract: eIF4E is the key regulator of protein translation and critical for translation. The oncogenic potential of tumorigenesis, which is highly contingent on cap-dependent eIF4E, also arises from the critical role in the nuclear export and cytosolic translation of oncogenic transcripts. Inhibition of Exportin1 (XPO1), which is the major nuclear export protein for eIF4E-bound oncoprotein mRNAs, results in decreased tumor cell growth in vitro and in vivo, suggesting that eIF4E is critical in multiple myeloma. Indeed, we found that eIF4E is overexpressed in myeloma cell lines and primary myeloma cells compared with normal plasma cells. Although stable overexpression of eIF4E in multiple myeloma cells significantly increases tumorigenesis, knockdown of eIF4E impairs multiple myeloma tumor progression in a human xenograft mouse model. Using a tet-on-inducible eIF4E-knockdown system, eIF4E downregulation blocks multiple myeloma tumor growth in vivo, correlating with decreased eIF4E expression. Further overexpression and knockdown of eIF4E revealed that eIF4E regulates translation of mRNAs with highly complex 5'-untranslated regions, such as c-MYC and C/EBPβ, and subsequently proliferation in multiple myeloma cells, but not in nonmalignant bone marrow stromal cells. Because many transcription factors that are critical for multiple myeloma proliferation exhibit a higher dependency on protein translation, eIF4E is an ideal and selective tool to target multiple myeloma cell growth. Mol Cancer Ther; 15(4); 711-9. ©2016 AACR.
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York.
authors.forename: Shirong
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York.
authors.forename: Jing
authors.initials: J
authors.lastname: Fu
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York.
authors.forename: Caisheng
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York.
authors.forename: Markus Y
authors.initials: MY
authors.lastname: Mapara
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York.
authors.forename: Shahzad
authors.initials: S
authors.lastname: Raza
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Hengst
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York. sl3440@columbia.edu.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lentzsch
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D000066630:Ectopic Gene Expression; D039561:Eukaryotic Initiation Factor-4E / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D016259:Genes, myc; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D058990:Molecular Targeted Therapy; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000099218:Interferon Regulatory Factor-4
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D022782:CCAAT-Enhancer-Binding Protein-beta; D039561:Eukaryotic Initiation Factor-4E; D050835:Interferon Regulatory Factors; D000099218:Interferon Regulatory Factor-4