Protein biosynthesis, a target of sorafenib, interferes with the unfolded protein response (UPR) and ferroptosis in hepatocellular carcinoma cells
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Chloé Sauzay1,2,*, Christophe Louandre1,*, Sandra Bodeau3, Frédéric Anglade1, Corinne Godin1,2, Zuzana Saidak4, Jean-Xavier Fontaine5, Cédric Usureau1, Nathalie Martin6, Roland Molinie5, Julie Pascal5, François Mesnard5, Olivier Pluquet6 and Antoine Galmiche1,2
1Laboratoire de Biochimie, Centre de Biologie Humaine, CHU Amiens Sud, France
2EA CHIMERE, Université de Picardie Jules Verne, Amiens, France
3Laboratoire de Pharmacologie, Centre de Biologie Humaine, CHU Amiens Sud, France
4Laboratoire d’Oncobiologie Moléculaire, Centre de Biologie Humaine, CHU Amiens Sud, France
5EA3900, Biologie des Plantes et Innovation, UFR de Pharmacie, Amiens, France
6Université de Lille, Institut Pasteur de Lille, CNRS UMR8161, M3T: Mechanisms of tumorigenesis and Targeted Therapies, Lille, France
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Antoine Galmiche, email: Galmiche.Antoine@chu-amiens.fr
Keywords: hepatocellular carcinoma; sorafenib; translation; unfolded protein response (UPR); ferroptosis
Received: June 09, 2017 Accepted: November 16, 2017 Published: January 03, 2018
Sorafenib is the first line treatment for advanced hepatocellular carcinoma (HCC). We explored its impact on the proteostasis of cancer cells, i.e. the processes that regulate the synthesis, maturation and turn-over of cellular proteins. We observed that sorafenib inhibits the production of the tumour marker alpha-foetoprotein (AFP) in two different HCC cell lines, an effect that correlated with a radical inhibition of protein biosynthesis. This effect was observed at clinically relevant concentrations of sorafenib and was not related to the effect of sorafenib on the transport of amino acids across the plasma membrane or the induction of the unfolded protein response (UPR). Instead, we observed that sorafenib inhibits translation initiation and the mechanistic target of rapamycin (mTOR) signaling cascade, as shown by the analysis of phosphorylation levels of the protein 4EBP1 (eukaryotic translation initiation factor 4E binding protein 1). We explored the consequences of this inhibition in HCC cells. We observed that overall sorafenib is a weak inducer of the UPR that can paradoxically prevent the UPR induced by tunicamycin. We also found no direct synergistic anticancer effect between sorafenib and various strategies that inhibit the UPR. In agreement with the possibility that translation inhibition might be an adaptive stress response in HCC cells, we noted that it protects cancer cell from ferroptosis, a form of oxidative necrosis. Our findings point to the modulation of protein biosynthesis and mTOR signaling as being important, yet complex determinants of the response of HCC cells to sorafenib.
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