PMID- 26403645
OWN - NLM
STAT- MEDLINE
DCOM- 20160510
LR  - 20220408
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 63
IP  - 1
DP  - 2016 Jan
TI  - Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in 
      hepatocellular carcinoma cells.
PG  - 173-84
LID - 10.1002/hep.28251 [doi]
AB  - Ferroptosis is a recently recognized form of regulated cell death caused by an 
      iron-dependent accumulation of lipid reactive oxygen species. However, the 
      molecular mechanisms regulating ferroptosis remain obscure. Here, we report that 
      nuclear factor erythroid 2-related factor 2 (NRF2) plays a central role in 
      protecting hepatocellular carcinoma (HCC) cells against ferroptosis. Upon 
      exposure to ferroptosis-inducing compounds (e.g., erastin, sorafenib, and 
      buthionine sulfoximine), p62 expression prevented NRF2 degradation and enhanced 
      subsequent NRF2 nuclear accumulation through inactivation of Kelch-like 
      ECH-associated protein 1. Additionally, nuclear NRF2 interacted with 
      transcriptional coactivator small v-maf avian musculoaponeurotic fibrosarcoma 
      oncogene homolog proteins such as MafG and then activated transcription of 
      quinone oxidoreductase-1, heme oxygenase-1, and ferritin heavy chain-1. Knockdown 
      of p62, quinone oxidoreductase-1, heme oxygenase-1, and ferritin heavy chain-1 by 
      RNA interference in HCC cells promoted ferroptosis in response to erastin and 
      sorafenib. Furthermore, genetic or pharmacologic inhibition of NRF2 
      expression/activity in HCC cells increased the anticancer activity of erastin and 
      sorafenib in vitro and in tumor xenograft models. CONCLUSION: These findings 
      demonstrate novel molecular mechanisms and signaling pathways of ferroptosis; the 
      status of NRF2 is a key factor that determines the therapeutic response to 
      ferroptosis-targeted therapies in HCC cells.
CI  - (c) 2015 by the American Association for the Study of Liver Diseases.
FAU - Sun, Xiaofang
AU  - Sun X
AD  - Center for DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical 
      University, Guangzhou, Guangdong, China.
FAU - Ou, Zhanhui
AU  - Ou Z
AD  - Center for DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical 
      University, Guangzhou, Guangdong, China.
FAU - Chen, Ruochan
AU  - Chen R
AD  - Department of Surgery, University of Pittsburgh Cancer Institute, University of 
      Pittsburgh, Pittsburgh, PA.
FAU - Niu, Xiaohua
AU  - Niu X
AD  - Center for DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical 
      University, Guangzhou, Guangdong, China.
FAU - Chen, De
AU  - Chen D
AD  - Center for DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical 
      University, Guangzhou, Guangdong, China.
FAU - Kang, Rui
AU  - Kang R
AD  - Department of Surgery, University of Pittsburgh Cancer Institute, University of 
      Pittsburgh, Pittsburgh, PA.
FAU - Tang, Daolin
AU  - Tang D
AD  - Center for DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical 
      University, Guangzhou, Guangdong, China.
AD  - Department of Surgery, University of Pittsburgh Cancer Institute, University of 
      Pittsburgh, Pittsburgh, PA.
LA  - eng
GR  - R01 CA160417/CA/NCI NIH HHS/United States
GR  - R01 GM115366/GM/NIGMS NIH HHS/United States
GR  - R01CA160417/CA/NCI NIH HHS/United States
GR  - R01GM115366/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20151126
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (KEAP1 protein, human)
RN  - 0 (Kelch-Like ECH-Associated Protein 1)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (P62 protein, human)
RN  - 0 (RNA-Binding Proteins)
RN  - E1UOL152H7 (Iron)
SB  - IM
MH  - Animals
MH  - Carcinoma, Hepatocellular/*metabolism/*pathology
MH  - Cell Death/*physiology
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/*physiology
MH  - Iron/*physiology
MH  - Kelch-Like ECH-Associated Protein 1
MH  - Liver Neoplasms/*metabolism/*pathology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - NF-E2-Related Factor 2/*physiology
MH  - RNA-Binding Proteins/*physiology
MH  - *Signal Transduction
MH  - Tumor Cells, Cultured
PMC - PMC4688087
MID - NIHMS725784
EDAT- 2015/09/26 06:00
MHDA- 2016/05/11 06:00
PMCR- 2017/01/01
CRDT- 2015/09/26 06:00
PHST- 2015/06/30 00:00 [received]
PHST- 2015/09/20 00:00 [accepted]
PHST- 2015/09/26 06:00 [entrez]
PHST- 2015/09/26 06:00 [pubmed]
PHST- 2016/05/11 06:00 [medline]
PHST- 2017/01/01 00:00 [pmc-release]
AID - 10.1002/hep.28251 [doi]
PST - ppublish
SO  - Hepatology. 2016 Jan;63(1):173-84. doi: 10.1002/hep.28251. Epub 2015 Nov 26.