Zismanov Victoria, Attar-Schneider Oshrat, Lishner Michael, Heffez Aizenfeld Rachel, Tartakover Matalon Shelly, Drucker Liat
Oncogenetic Laboratory, Meir Medical Center, Kfar Saba, Israel.
Geriatric Department, Meir Medical Center, Kfar Saba, Israel.
Int J Oncol. 2015 Feb;46(2):860-70. doi: 10.3892/ijo.2014.2774. Epub 2014 Nov 24.
Intensive protein synthesis is a unique and differential trait of the multiple myeloma (MM) cells. Previously we showed that tetraspanin overexpression in MM cell lines attenuated mTOR and PI3K cascades, induced protein synthesis, activated unfolded protein response (UPR), and caused autophagic death, all suggesting breach of proteostasis. Here we assessed the role of translation initiation in the tetraspanin‑induced MM cell death with emphasis on eIF4E translation initiation factor. We showed tetraspanins attenuated peIF4E and its targets [c‑Myc, cyclin D1 (cycD1)]; eIF4E attenuation was Akt-dependent. eIF4E inhibition in MM cells [bone marrow (BM), lines] by siRNA and/or the anti‑viral drug and competitive eIF4E inhibitor ribavirin (RBV) deleteriously affected MM cells in a similar manner to the overexpression of tetraspanins. Furthermore, combined application of RBV and velcade had a synergistic anti‑MM effect. Our results demonstrate that breach of proteostasis via eIF4E inhibition is an attractive therapeutic approach that may be relatively easily achieved by employing RBV, making this strategy readily translatable into the clinic.
强烈的蛋白质合成是多发性骨髓瘤（MM）细胞的一种独特且有差异的特征。此前我们发现，MM细胞系中四跨膜蛋白的过表达会减弱mTOR和PI3K级联反应，诱导蛋白质合成，激活未折叠蛋白反应（UPR），并导致自噬性死亡，所有这些都表明蛋白质稳态遭到破坏。在此，我们评估了翻译起始在四跨膜蛋白诱导的MM细胞死亡中的作用，重点关注真核翻译起始因子4E（eIF4E）。我们发现四跨膜蛋白会减弱磷酸化eIF4E及其靶点[c-Myc、细胞周期蛋白D1（cycD1）]；eIF4E的减弱依赖于Akt。通过小干扰RNA（siRNA）和/或抗病毒药物以及竞争性eIF4E抑制剂利巴韦林（RBV）抑制MM细胞[骨髓（BM）、细胞系]中的eIF4E，会以与四跨膜蛋白过表达类似的方式对MM细胞产生有害影响。此外，联合应用RBV和万珂具有协同抗MM作用。我们的结果表明，通过抑制eIF4E破坏蛋白质稳态是一种有吸引力的治疗方法，通过使用RBV可能相对容易实现，这使得该策略易于转化应用于临床。
