PMID- 27211800
OWN - NLM
STAT- MEDLINE
DCOM- 20171002
LR  - 20220410
IS  - 1875-5666 (Electronic)
IS  - 1566-5240 (Print)
IS  - 1566-5240 (Linking)
VI  - 16
IP  - 6
DP  - 2016
TI  - The Role of the PERK/eIF2alpha/ATF4/CHOP Signaling Pathway in Tumor Progression 
      During Endoplasmic Reticulum Stress.
PG  - 533-44
AB  - Hypoxia is a major hallmark of the tumor microenvironment that is strictly 
      associated with rapid cancer progression and induction of metastasis. Hypoxia 
      inhibits disulfide bond formation and impairs protein folding in the Endoplasmic 
      Reticulum (ER). The stress in the ER induces the activation of Unfolded Protein 
      Response (UPR) pathways via the induction of protein kinase RNA-like endoplasmic 
      reticulum kinase (PERK). As a result, the level of phosphorylated Eukaryotic 
      Initiation Factor 2 alpha (eIF2alpha) is markedly elevated, resulting in the 
      promotion of a pro-adaptive signaling pathway by the inhibition of global protein 
      synthesis and selective translation of Activating Transcription Factor 4 (ATF4). 
      On the contrary, during conditions of prolonged ER stress, pro-adaptive responses 
      fail and apoptotic cell death ensues. Interestingly, similar to the activity of 
      the mitochondria, the ER may also directly activate the apoptotic pathway through 
      ER stress-mediated leakage of calcium into the cytoplasm that leads to the 
      activation of death effectors. Apoptotic cell death also ensues by ATF4-CHOP- 
      mediated induction of several pro-apoptotic genes and suppression of the 
      synthesis of anti-apoptotic Bcl-2 proteins. Advancing molecular insight into the 
      transition of tumor cells from adaptation to apoptosis under hypoxia-induced ER 
      stress may provide answers on how to overcome the limitations of current 
      anti-tumor therapies. Targeting components of the UPR pathways may provide more 
      effective elimination of tumor cells and as a result, contribute to the 
      development of more promising anti-tumor therapeutic agents.
FAU - Rozpedek, W
AU  - Rozpedek W
FAU - Pytel, D
AU  - Pytel D
AD  - Department of Biochemistry and Molecular Biology, Medical University of South 
      Carolina, Hollings Cancer Center, HCC-709, 86 Jonathan Lucas Street, Charleston, 
      SC 29425, USA. pytel@musc.edu.
FAU - Mucha, B
AU  - Mucha B
FAU - Leszczynska, H
AU  - Leszczynska H
FAU - Diehl, J A
AU  - Diehl JA
FAU - Majsterek, I
AU  - Majsterek I
AD  - Department of Clinical Chemistry and Biochemistry, Military-Medical Faculty, 
      Medical University of Lodz, Hallera 1, 90-647 Lodz, Poland. 
      ireneusz.majsterek@umed.lodz.pl.
LA  - eng
GR  - P01 CA104838/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PL  - Netherlands
TA  - Curr Mol Med
JT  - Current molecular medicine
JID - 101093076
RN  - 0 (ATF4 protein, human)
RN  - 0 (DDIT3 protein, human)
RN  - 0 (Eukaryotic Initiation Factor-2)
RN  - 145891-90-3 (Activating Transcription Factor 4)
RN  - 147336-12-7 (Transcription Factor CHOP)
RN  - EC 2.7.11.1 (EIF2AK3 protein, human)
RN  - EC 2.7.11.1 (eIF-2 Kinase)
SB  - IM
MH  - Activating Transcription Factor 4/*genetics/metabolism
MH  - Animals
MH  - Apoptosis
MH  - Cell Hypoxia
MH  - Cell Transformation, Neoplastic/genetics/metabolism/pathology
MH  - Disease Progression
MH  - Endoplasmic Reticulum/metabolism
MH  - Endoplasmic Reticulum Stress/genetics
MH  - Eukaryotic Initiation Factor-2/*genetics/metabolism
MH  - *Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Neoplasms/*genetics/metabolism/pathology
MH  - Signal Transduction
MH  - Transcription Factor CHOP/*genetics/metabolism
MH  - Unfolded Protein Response
MH  - eIF-2 Kinase/*genetics/metabolism
PMC - PMC5008685
MID - NIHMS804115
EDAT- 2016/05/24 06:00
MHDA- 2017/10/03 06:00
PMCR- 2016/09/01
CRDT- 2016/05/24 06:00
PHST- 2016/03/07 00:00 [received]
PHST- 2016/05/08 00:00 [revised]
PHST- 2016/05/20 00:00 [accepted]
PHST- 2016/05/24 06:00 [entrez]
PHST- 2016/05/24 06:00 [pubmed]
PHST- 2017/10/03 06:00 [medline]
PHST- 2016/09/01 00:00 [pmc-release]
AID - CMM-EPUB-75880 [pii]
AID - 10.2174/1566524016666160523143937 [doi]
PST - ppublish
SO  - Curr Mol Med. 2016;16(6):533-44. doi: 10.2174/1566524016666160523143937.