The many ways to inhibit translation by Sorafenib in liver cancer cells.

IF 3.7 2区 生物学 Q3 CELL BIOLOGY
Laura Contreras, Sara Ricciardi, Stefano Biffo, Jordi Muntané, Jesús de la Cruz
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引用次数: 0

Abstract

Sorafenib targets various tyrosine kinase receptors, inhibiting cell growth and proliferation, angiogenesis and metastasis in tumour cells. It is used to treat certain types of cancers including renal, thyroid and liver (hepatocellular carcinoma) cancers. Although Sorafenib is approved for advanced hepatocellular carcinoma, it only extends patient´s lives by a few months, highlighting the urgent need to better understand how it works and to develop more effective treatments. Sorafenib specifically inhibits translation initiation in hepatocellular carcinoma cells. Herein, we revealed that this inhibition results, at least, from the activation of PERK, triggering a stress response that leads to eIF2α phosphorylation, the inhibition of MNK1a-signalling-dependent eIF4E phosphorylation, and the aberrant assembly of the canonical eIF4F complex. Sorafenib also inhibits the ERK1/2 MAPK signalling in HepG2 cells. However, the mTORC1 pathway does appear to play a pivotal role in Sorafenib-dependent translation inhibition, as revealed by the phosphorylation levels of RPS6 and 4EBP1 proteins and the effects on translation of gene silencing 4EBP1/2 in Sorafenib-treated cells. Translation inhibition correlates with reduced production of cancer-promoting proteins like Cyclin D1 and c-Myc. Overexpression of the phosphomimetic eIF4E-S209D variant, which constitutively activates eIF4E, shows that inhibition of eIF4E phosphorylation directly causes Cyclin D1 down-regulation and cell-cycle delay in Sorafenib-treated cells. Taken together, our results confirm that Sorafenib induces translation reprogramming, whose understanding is crucial for improving its efficacy as a cancer therapy.

索拉非尼抑制肝癌细胞翻译的多种途径。
索拉非尼靶向多种酪氨酸激酶受体,抑制肿瘤细胞的生长和增殖、血管生成和转移。它被用来治疗某些类型的癌症,包括肾癌、甲状腺癌和肝癌。尽管索拉非尼被批准用于晚期肝细胞癌,但它只能延长患者的生命几个月,这凸显了迫切需要更好地了解其工作原理并开发更有效的治疗方法。索拉非尼特异性抑制肝癌细胞的翻译起始。在这里,我们揭示了这种抑制至少是由于PERK的激活,引发应激反应,导致eIF2α磷酸化,抑制mnk1a信号依赖性eIF4E磷酸化,以及典型eIF4F复合物的异常组装。索拉非尼还能抑制HepG2细胞中的ERK1/2 MAPK信号传导。然而,在sorafenib处理的细胞中,RPS6和4EBP1蛋白的磷酸化水平以及对基因沉默4EBP1/2翻译的影响显示,mTORC1通路似乎在sorafenib依赖性翻译抑制中发挥关键作用。翻译抑制与促癌蛋白如Cyclin D1和c-Myc的产生减少有关。过表达的拟磷eIF4E- s209d变体,组成性地激活eIF4E,表明抑制eIF4E磷酸化直接导致索拉非尼处理的细胞中Cyclin D1下调和细胞周期延迟。综上所述,我们的研究结果证实索拉非尼诱导翻译重编程,这对于提高其作为癌症治疗的疗效至关重要。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular and Cellular Biochemistry
Molecular and Cellular Biochemistry 生物-细胞生物学
CiteScore
8.30
自引率
2.30%
发文量
293
审稿时长
1.7 months
期刊介绍: Molecular and Cellular Biochemistry: An International Journal for Chemical Biology in Health and Disease publishes original research papers and short communications in all areas of the biochemical sciences, emphasizing novel findings relevant to the biochemical basis of cellular function and disease processes, as well as the mechanics of action of hormones and chemical agents. Coverage includes membrane transport, receptor mechanism, immune response, secretory processes, and cytoskeletal function, as well as biochemical structure-function relationships in the cell. In addition to the reports of original research, the journal publishes state of the art reviews. Specific subjects covered by Molecular and Cellular Biochemistry include cellular metabolism, cellular pathophysiology, enzymology, ion transport, lipid biochemistry, membrane biochemistry, molecular biology, nuclear structure and function, and protein chemistry.
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