De Gassart Aude, Demaria Olivier, Panes Rébecca, Zaffalon Léa, Ryazanov Alexey G, Gilliet Michel, Martinon Fabio
Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
Department of Dermatology, CHUV, Lausanne, Switzerland.
EMBO Rep. 2016 Oct;17(10):1471-1484. doi: 10.15252/embr.201642194. Epub 2016 Aug 29.
Activation of the elongation factor 2 kinase (eEF2K) leads to the phosphorylation and inhibition of the elongation factor eEF2, reducing mRNA translation rates. Emerging evidence indicates that the regulation of factors involved in protein synthesis may be critical for controlling diverse biological processes including cancer progression. Here we show that inhibitors of the HIV aspartyl protease (HIV-PIs), nelfinavir in particular, trigger a robust activation of eEF2K leading to the phosphorylation of eEF2. Beyond its anti-viral effects, nelfinavir has antitumoral activity and promotes cell death. We show that nelfinavir-resistant cells specifically evade eEF2 inhibition. Decreased cell viability induced by nelfinavir is impaired in cells lacking eEF2K. Moreover, nelfinavir-mediated anti-tumoral activity is severely compromised in eEF2K-deficient engrafted tumors in vivo Our findings imply that exacerbated activation of eEF2K is detrimental for tumor survival and describe a mechanism explaining the anti-tumoral properties of HIV-PIs.
真核生物延伸因子2激酶(eEF2K)的激活会导致延伸因子eEF2的磷酸化及抑制,从而降低mRNA的翻译速率。新出现的证据表明,参与蛋白质合成的因子的调控对于控制包括癌症进展在内的多种生物学过程可能至关重要。在此我们表明,HIV天冬氨酸蛋白酶抑制剂(HIV-PIs),尤其是奈非那韦,会引发eEF2K的强烈激活,导致eEF2磷酸化。除了其抗病毒作用外,奈非那韦还具有抗肿瘤活性并促进细胞死亡。我们发现,对奈非那韦耐药的细胞能特异性逃避eEF2的抑制。在缺乏eEF2K的细胞中,奈非那韦诱导的细胞活力下降受到损害。此外,在体内eEF2K缺陷的移植瘤中,奈非那韦介导的抗肿瘤活性严重受损。我们的研究结果表明,eEF2K的过度激活对肿瘤存活有害,并描述了一种解释HIV-PIs抗肿瘤特性的机制。