Li Shirong, Fu Jing, Lu Caisheng, Mapara Markus Y, Raza Shahzad, Hengst Ulrich, Lentzsch Suzanne
Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York.
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York.
Mol Cancer Ther. 2016 Apr;15(4):711-9. doi: 10.1158/1535-7163.MCT-15-0798. Epub 2016 Mar 3.
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.
真核生物翻译起始因子4E（eIF4E）是蛋白质翻译的关键调节因子，对翻译过程至关重要。肿瘤发生的致癌潜力高度依赖于帽依赖性eIF4E，这也源于其在致癌转录本的核输出和胞质翻译中的关键作用。抑制输出蛋白1（XPO1），它是与eIF4E结合的癌蛋白mRNA的主要核输出蛋白，会导致体外和体内肿瘤细胞生长减少，这表明eIF4E在多发性骨髓瘤中至关重要。事实上，我们发现与正常浆细胞相比，eIF4E在骨髓瘤细胞系和原发性骨髓瘤细胞中过表达。虽然在多发性骨髓瘤细胞中稳定过表达eIF4E会显著增加肿瘤发生，但在人异种移植小鼠模型中敲低eIF4E会损害多发性骨髓瘤的肿瘤进展。使用四环素诱导的eIF4E敲低系统，eIF4E下调会阻断体内多发性骨髓瘤肿瘤生长，这与eIF4E表达降低相关。进一步对eIF4E进行过表达和敲低表明，eIF4E调节具有高度复杂5'非翻译区的mRNA的翻译，如c-MYC和C/EBPβ，随后调节多发性骨髓瘤细胞的增殖，但不调节非恶性骨髓基质细胞的增殖。由于许多对多发性骨髓瘤增殖至关重要的转录因子对蛋白质翻译有更高的依赖性，eIF4E是靶向多发性骨髓瘤细胞生长的理想且选择性的工具。《分子癌症治疗》；15（4）；711 - 9。©2016美国癌症研究协会。
