Demosthenous Christos, Han Jing Jing, Stenson Mary J, Maurer Matthew J, Wellik Linda E, Link Brian, Hege Kristen, Dogan Ahmet, Sotomayor Eduardo, Witzig Thomas, Gupta Mamta
Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
Department of Internal Medicine, University of Iowa College of Medicine, IA, USA.
Oncotarget. 2015 Apr 20;6(11):9488-501. doi: 10.18632/oncotarget.3378.
Deregulated mRNA translation has been implicated in disease development and in part is controlled by a eukaryotic initiation complex eIF4F (composed of eIF4E, eIF4G and eIF4A). We demonstrate here that the cap bound fraction from lymphoma cells was enriched with eIF4G and eIF4E indicating that lymphoma cells exist in an activated translational state. Moreover, 77% (110/142) of diffuse large B cell lymphoma tumors expressed eIF4E and this was associated with an inferior event free survival. Over-expression of wild-type eIF4E (eIF4E(WT)) but not cap-mutant eIF4E (eIF4E(cap mutant)) increased the activation of the eIF4F complex. Treatment with the active-site dual mTOR inhibitor CC214-1 reduced the level of the eIF4F complex by decreasing the cap bound fraction of eIF4G and increasing the levels of 4E-BP1. CC214-1 inhibited both the cap dependent and global protein translation. CC214-1 inhibited c-Myc, and cyclin D3 translation by decreasing polysomal fractions from lymphoma cells. Inhibition of eIF4E with shRNA further decreased the CC214-1 induced inhibition of the eIF4F complex, c-Myc, cyclin D3 translation, and colony formation. These studies demonstrate that the eIF4F complex is deregulated in aggressive lymphoma and that dual mTOR therapy has therapeutic potential in these patients.
失调的mRNA翻译与疾病发展有关，部分受真核生物起始复合物eIF4F（由eIF4E、eIF4G和eIF4A组成）控制。我们在此证明，淋巴瘤细胞中与帽结合的部分富含eIF4G和eIF4E，这表明淋巴瘤细胞处于激活的翻译状态。此外，77%（110/142）的弥漫性大B细胞淋巴瘤肿瘤表达eIF4E，这与较差的无事件生存率相关。野生型eIF4E（eIF4E(WT)）而非帽突变型eIF4E（eIF4E(帽突变体)）的过表达增加了eIF4F复合物的激活。用活性位点双mTOR抑制剂CC214-1处理可通过降低eIF4G的帽结合部分并增加4E-BP1的水平来降低eIF4F复合物的水平。CC214-1抑制帽依赖性和整体蛋白质翻译。CC214-1通过降低淋巴瘤细胞的多核糖体部分来抑制c-Myc和细胞周期蛋白D3的翻译。用shRNA抑制eIF4E进一步降低了CC214-1诱导的对eIF4F复合物、c-Myc、细胞周期蛋白D3翻译和集落形成的抑制。这些研究表明，eIF4F复合物在侵袭性淋巴瘤中失调，双mTOR疗法对这些患者具有治疗潜力。
