PMID- 31507082
OWN - NLM
STAT- MEDLINE
DCOM- 20200910
LR  - 20231213
IS  - 1582-4934 (Electronic)
IS  - 1582-1838 (Print)
IS  - 1582-1838 (Linking)
VI  - 23
IP  - 11
DP  - 2019 Nov
TI  - Sigma-1 receptor protects against ferroptosis in hepatocellular carcinoma cells.
PG  - 7349-7359
LID - 10.1111/jcmm.14594 [doi]
AB  - Sigma-1 receptor (S1R) regulates reactive oxygen species (ROS) accumulation via 
      nuclear factor erythroid 2-related factor 2 (NRF2), which plays a vital role in 
      ferroptosis. Sorafenib is a strong inducer of ferroptosis but not of apoptosis. 
      However, the mechanism of sorafenib-induced ferroptosis in hepatocellular 
      carcinoma (HCC) remains unclear. In this study, we found for the first time that 
      sorafenib induced most of S1Rs away from nucleus compared to control groups in 
      Huh-7 cells, and ferrostatin-1 completely blocked the translocation. S1R protein 
      expression, but not mRNA expression, in HCC cells was significantly up-regulated 
      by sorafenib. Knockdown of NRF2, but not of p53 or hypoxia-inducible factor 
      1-alpha (HIF1alpha), markedly induced S1R mRNA expression in HCC cells. Inhibition of 
      S1R (by RNAi or antagonists) increased sorafenib-induced HCC cell death in vitro 
      and in vivo. Knockdown of S1R blocked the expression of glutathione peroxidase 4 
      (GPX4), one of the core targets of ferroptosis, in vitro and in vivo. Iron 
      metabolism and lipid peroxidation increased in the S1R knockdown groups treated 
      with sorafenib compared to the control counterpart. Ferritin heavy chain 1 (FTH1) 
      and transferrin receotor protein 1 (TFR1), both of which are critical for iron 
      metabolism, were markedly up-regulated in HCC cells treated with erastin and 
      sorafenib, whereas knockdown of S1R inhibited these increases. In conclusion, we 
      demonstrate that S1R protects HCC cells against sorafenib and subsequent 
      ferroptosis. A better understanding of the role of S1R in ferroptosis may provide 
      novel insight into this biological process.
CI  - (c) 2019 The Authors. Journal of Cellular and Molecular Medicine published by John 
      Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
FAU - Bai, Tao
AU  - Bai T
AD  - Department of Hepatobiliary and Pancreatic Surgery, School of Medicine, The First 
      Affiliated Hospital of Zhengzhou University, Institute of Hepatobiliary and 
      Pancreatic Diseases, Zhengzhou University, Zhengzhou, China.
FAU - Lei, Pengxu
AU  - Lei P
AD  - Department of Hepatobiliary and Pancreatic Surgery, School of Medicine, The First 
      Affiliated Hospital of Zhengzhou University, Institute of Hepatobiliary and 
      Pancreatic Diseases, Zhengzhou University, Zhengzhou, China.
FAU - Zhou, Hao
AU  - Zhou H
AD  - Department of Hepatobiliary and Pancreatic Surgery, School of Medicine, The First 
      Affiliated Hospital of Zhengzhou University, Institute of Hepatobiliary and 
      Pancreatic Diseases, Zhengzhou University, Zhengzhou, China.
FAU - Liang, Ruopeng
AU  - Liang R
AD  - Department of Hepatobiliary and Pancreatic Surgery, School of Medicine, The First 
      Affiliated Hospital of Zhengzhou University, Institute of Hepatobiliary and 
      Pancreatic Diseases, Zhengzhou University, Zhengzhou, China.
FAU - Zhu, Rongtao
AU  - Zhu R
AD  - Department of Hepatobiliary and Pancreatic Surgery, School of Medicine, The First 
      Affiliated Hospital of Zhengzhou University, Institute of Hepatobiliary and 
      Pancreatic Diseases, Zhengzhou University, Zhengzhou, China.
FAU - Wang, Weijie
AU  - Wang W
AD  - Department of Hepatobiliary and Pancreatic Surgery, School of Medicine, The First 
      Affiliated Hospital of Zhengzhou University, Institute of Hepatobiliary and 
      Pancreatic Diseases, Zhengzhou University, Zhengzhou, China.
FAU - Zhou, Lin
AU  - Zhou L
AD  - Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou 
      University, Zhengzhou, China.
FAU - Sun, Yuling
AU  - Sun Y
AUID- ORCID: 0000-0001-5289-4673
AD  - Department of Hepatobiliary and Pancreatic Surgery, School of Medicine, The First 
      Affiliated Hospital of Zhengzhou University, Institute of Hepatobiliary and 
      Pancreatic Diseases, Zhengzhou University, Zhengzhou, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190910
PL  - England
TA  - J Cell Mol Med
JT  - Journal of cellular and molecular medicine
JID - 101083777
RN  - 0 (Piperazines)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Receptors, sigma)
RN  - 0 (erastin)
RN  - 9ZOQ3TZI87 (Sorafenib)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects/physiology
MH  - Carcinoma, Hepatocellular/drug therapy/*metabolism
MH  - Cell Death/drug effects/physiology
MH  - Cell Line, Tumor
MH  - Ferroptosis/drug effects/*physiology
MH  - Hep G2 Cells
MH  - Humans
MH  - Lipid Peroxidation/drug effects/physiology
MH  - Liver Neoplasms/drug therapy/*metabolism
MH  - Mice
MH  - Piperazines/pharmacology
MH  - Reactive Oxygen Species/metabolism
MH  - Receptors, sigma/*metabolism
MH  - Sorafenib/pharmacology
MH  - Up-Regulation/drug effects/physiology
MH  - Sigma-1 Receptor
PMC - PMC6815844
OTO - NOTNLM
OT  - ferroptosis
OT  - hepatocellular carcinoma
OT  - sigma-1 receptor
OT  - sorafenib
COIS- The authors declare no conflicts of interest.
EDAT- 2019/09/12 06:00
MHDA- 2020/09/12 06:00
PMCR- 2019/11/01
CRDT- 2019/09/12 06:00
PHST- 2019/03/01 00:00 [received]
PHST- 2019/07/23 00:00 [accepted]
PHST- 2019/09/12 06:00 [pubmed]
PHST- 2020/09/12 06:00 [medline]
PHST- 2019/09/12 06:00 [entrez]
PHST- 2019/11/01 00:00 [pmc-release]
AID - JCMM14594 [pii]
AID - 10.1111/jcmm.14594 [doi]
PST - ppublish
SO  - J Cell Mol Med. 2019 Nov;23(11):7349-7359. doi: 10.1111/jcmm.14594. Epub 2019 Sep 
      10.