Miluzio Annarita, Oliveto Stefania, Pesce Elisa, Mutti Luciano, Murer Bruno, Grosso Stefano, Ricciardi Sara, Brina Daniela, Biffo Stefano
Molecular Histology and Cell Growth Unit, Istituto Nazionale Genetica Molecolare, "Romeo ed Enrica Invernizzi", Milano, Italy.
Dipartimento di Scienze e Innovazione Tecnologica, University of Eastern Piedmont, Alessandria, Italy.
Oncotarget. 2015 Nov 10;6(35):37471-85. doi: 10.18632/oncotarget.5462.
eIF6 is an antiassociation factor that regulates the availability of active 80S. Its activation is driven by the RACK1/PKCβ axis, in a mTORc1 independent manner. We previously described that eIF6 haploinsufficiency causes a striking survival in the Eμ-Myc mouse lymphoma model, with lifespans extended up to 18 months. Here we screen for eIF6 expression in human cancers. We show that Malignant Pleural Mesothelioma tumors (MPM) and a MPM cell line (REN cells) contain high levels of hyperphosphorylated eIF6. Enzastaurin is a PKC beta inhibitor used in clinical trials. We prove that Enzastaurin treatment decreases eIF6 phosphorylation rate, but not eIF6 protein stability. The growth of REN, in vivo, and metastasis are reduced by either Enzastaurin treatment or eIF6 shRNA. Molecular analysis reveals that eIF6 manipulation affects the metabolic status of malignant mesothelioma cells. Less glycolysis and less ATP content are evident in REN cells depleted for eIF6 or treated with Enzastaurin (Anti-Warburg effect). We propose that eIF6 is necessary for malignant mesothelioma growth, in vivo, and can be targeted by kinase inhibitors.
真核生物翻译起始因子6（eIF6）是一种调节活性80S核糖体可用性的抗结合因子。其激活由RACK1/PKCβ轴驱动，且不依赖于雷帕霉素靶蛋白复合体1（mTORc1）。我们之前描述过，在Eμ-Myc小鼠淋巴瘤模型中，eIF6单倍体不足会显著延长生存期，寿命延长可达18个月。在此，我们对人类癌症中的eIF6表达进行筛选。我们发现恶性胸膜间皮瘤（MPM）肿瘤和一种MPM细胞系（REN细胞）含有高水平的过度磷酸化eIF6。恩扎妥林是一种用于临床试验的PKCβ抑制剂。我们证明恩扎妥林治疗可降低eIF6磷酸化速率，但不影响eIF6蛋白稳定性。恩扎妥林治疗或eIF6短发夹RNA（shRNA）均可降低REN细胞在体内的生长和转移。分子分析表明，对eIF6的调控会影响恶性间皮瘤细胞的代谢状态。在eIF6缺失或用恩扎妥林处理的REN细胞中，糖酵解减少和ATP含量降低更为明显（抗瓦伯格效应）。我们提出，eIF6是恶性间皮瘤在体内生长所必需的，并且可以被激酶抑制剂靶向作用。
