Sorafenib-associated translation reprogramming in hepatocellular carcinoma cells
Sorafenib (Sfb) is a multikinase inhibitor indicated as an oral first-line chemotherapeutic drug for patients with advanced hepatocellular carcinoma (HCC) that has been shown to increase very modestly life expectancy. We have shown that Sfb inhibits protein synthesis at the level of initiation in cancer cells. However, the global snapshot of mRNA translation following Sorafenib-treatment has not been explored so far. In this study, we performed a genome-wide polysome profiling analysis in Sfb-treated HCC cells and demonstrated that, despite global translation repression, a set of different genes remain efficiently translated or are even translationally induced. We reveal that, in response to Sfb inhibition, translation is tuned by established mRNA cis-acting elements and the corresponding protein factors that recognize them, including DAP5 and ARE-binding proteins. At the level of biological processes, Sfb leads to the translational down-regulation of key cellular activities, such as those related to the mitochondrial metabolism and the collagen synthesis, and the translational up-regulation of pathways associated with the adaptation and survival of cells in response to the Sfb-induced stress. Our findings indicate that Sfb induces an adaptive reprogramming of translation and provide valuable information that can facilitate the analysis of other drugs for the development of novel strategies to optimize Sfb therapy. Overall design: RiboSeq experiment of Sorafenib and Control treated HepG Hepatocascinoma cell line. Samples are divided in Low polysome (F1) and high polysome (F2) fractions. Triplicate experiments.