PMID- 29492203
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20191120
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 9
IP  - 9
DP  - 2018 Feb 2
TI  - Protein biosynthesis, a target of sorafenib, interferes with the unfolded protein 
      response (UPR) and ferroptosis in hepatocellular carcinoma cells.
PG  - 8400-8414
LID - 10.18632/oncotarget.23843 [doi]
AB  - 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.
FAU - Sauzay, Chloe
AU  - Sauzay C
AD  - Laboratoire de Biochimie, Centre de Biologie Humaine, CHU Amiens Sud, France.
AD  - EA CHIMERE, Universite de Picardie Jules Verne, Amiens, France.
FAU - Louandre, Christophe
AU  - Louandre C
AD  - Laboratoire de Biochimie, Centre de Biologie Humaine, CHU Amiens Sud, France.
FAU - Bodeau, Sandra
AU  - Bodeau S
AD  - Laboratoire de Pharmacologie, Centre de Biologie Humaine, CHU Amiens Sud, France.
FAU - Anglade, Frederic
AU  - Anglade F
AD  - Laboratoire de Biochimie, Centre de Biologie Humaine, CHU Amiens Sud, France.
FAU - Godin, Corinne
AU  - Godin C
AD  - Laboratoire de Biochimie, Centre de Biologie Humaine, CHU Amiens Sud, France.
AD  - EA CHIMERE, Universite de Picardie Jules Verne, Amiens, France.
FAU - Saidak, Zuzana
AU  - Saidak Z
AD  - Laboratoire d'Oncobiologie Moleculaire, Centre de Biologie Humaine, CHU Amiens 
      Sud, France.
FAU - Fontaine, Jean-Xavier
AU  - Fontaine JX
AD  - EA3900, Biologie des Plantes et Innovation, UFR de Pharmacie, Amiens, France.
FAU - Usureau, Cedric
AU  - Usureau C
AD  - Laboratoire de Biochimie, Centre de Biologie Humaine, CHU Amiens Sud, France.
FAU - Martin, Nathalie
AU  - Martin N
AD  - Universite de Lille, Institut Pasteur de Lille, CNRS UMR8161, M3T: Mechanisms of 
      tumorigenesis and Targeted Therapies, Lille, France.
FAU - Molinie, Roland
AU  - Molinie R
AD  - EA3900, Biologie des Plantes et Innovation, UFR de Pharmacie, Amiens, France.
FAU - Pascal, Julie
AU  - Pascal J
AD  - EA3900, Biologie des Plantes et Innovation, UFR de Pharmacie, Amiens, France.
FAU - Mesnard, Francois
AU  - Mesnard F
AD  - EA3900, Biologie des Plantes et Innovation, UFR de Pharmacie, Amiens, France.
FAU - Pluquet, Olivier
AU  - Pluquet O
AD  - Universite de Lille, Institut Pasteur de Lille, CNRS UMR8161, M3T: Mechanisms of 
      tumorigenesis and Targeted Therapies, Lille, France.
FAU - Galmiche, Antoine
AU  - Galmiche A
AD  - Laboratoire de Biochimie, Centre de Biologie Humaine, CHU Amiens Sud, France.
AD  - EA CHIMERE, Universite de Picardie Jules Verne, Amiens, France.
LA  - eng
PT  - Journal Article
DEP - 20180103
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
PMC - PMC5823558
OTO - NOTNLM
OT  - ferroptosis
OT  - hepatocellular carcinoma
OT  - sorafenib
OT  - translation
OT  - unfolded protein response (UPR)
COIS- CONFLICTS OF INTEREST None.
EDAT- 2018/03/02 06:00
MHDA- 2018/03/02 06:01
PMCR- 2018/02/02
CRDT- 2018/03/02 06:00
PHST- 2017/06/09 00:00 [received]
PHST- 2017/11/16 00:00 [accepted]
PHST- 2018/03/02 06:00 [entrez]
PHST- 2018/03/02 06:00 [pubmed]
PHST- 2018/03/02 06:01 [medline]
PHST- 2018/02/02 00:00 [pmc-release]
AID - 23843 [pii]
AID - 10.18632/oncotarget.23843 [doi]
PST - epublish
SO  - Oncotarget. 2018 Jan 3;9(9):8400-8414. doi: 10.18632/oncotarget.23843. 
      eCollection 2018 Feb 2.