PMID- 22788551
OWN - NLM
STAT- MEDLINE
DCOM- 20130104
LR  - 20211021
IS  - 1423-0127 (Electronic)
IS  - 1021-7770 (Print)
IS  - 1021-7770 (Linking)
VI  - 19
IP  - 1
DP  - 2012 Jul 12
TI  - Insulin receptor substrate-1 prevents autophagy-dependent cell death caused by 
      oxidative stress in mouse NIH/3T3 cells.
PG  - 64
LID - 10.1186/1423-0127-19-64 [doi]
AB  - BACKGROUND: Insulin receptor substrate (IRS)-1 is associated with tumorigenesis; 
      its levels are elevated in several human cancers. IRS-1 protein binds to several 
      oncogene proteins. Oxidative stress and reactive oxygen species (ROS) are 
      involved in the initiation and progression of cancers. Cancer cells produce 
      greater levels of ROS than normal cells do because of increased metabolic 
      stresses. However, excessive production of ROS kills cancer cells. Autophagy 
      usually serves as a survival mechanism in response to stress conditions, but 
      excessive induction of autophagy results in cell death. In addition to inducing 
      necrosis and apoptosis, ROS induces autophagic cell death. ROS inactivates IRS-1 
      mediated signaling and reduces intracellular IRS-1 concentrations. Thus, there is 
      a complex relationship between IRS-1, ROS, autophagy, and cancer. It is not fully 
      understood how cancer cells grow rapidly and survive in the presence of high ROS 
      levels. METHODS AND RESULTS: In this study, we established mouse NIH/3T3 cells 
      that overexpressed IRS-1, so mimicking cancers with increased IRS-1 expression 
      levels; we found that the IRS-1 overexpressing cells grow more rapidly than 
      control cells do. Treatment of cells with glucose oxidase (GO) provided a 
      continuous source of ROS; low dosages of GO promoted cell growth, while high 
      doses induced cell death. Evidence for GO induced autophagy includes increased 
      levels of isoform B-II microtubule-associated protein 1 light chain 3 (LC3), 
      aggregation of green fluorescence protein-tagged LC3, and increased numbers of 
      autophagic vacuoles in cells. Overexpression of IRS-1 resulted in inhibition of 
      basal autophagy, and reduced oxidative stress-induced autophagy and cell death. 
      ROS decreased the mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 
      kinase signaling, while overexpression of IRS-1 attenuated this inhibition. 
      Knockdown of autophagy-related gene 5 inhibited basal autophagy and diminished 
      oxidative stress-induced autophagy and cell death. CONCLUSION: Our results 
      suggest that overexpression of IRS-1 promotes cells growth, inhibits basal 
      autophagy, reduces oxidative stress-induced autophagy, and diminishes oxidative 
      stress-mediated autophagy-dependent cell death. ROS-mediated autophagy may occur 
      via inhibition of IRS-1/phosphatidylinositol 3-kinase/mTOR signaling. Our data 
      afford a plausible explanation for IRS-1 involvement in tumor initiation and 
      progression.
FAU - Chan, Shih-Hung
AU  - Chan SH
AD  - Institute of Clinical Medicine, College of Medicine, National Cheng Kung 
      University, Tainan, Taiwan.
FAU - Kikkawa, Ushio
AU  - Kikkawa U
FAU - Matsuzaki, Hidenori
AU  - Matsuzaki H
FAU - Chen, Jyh-Hong
AU  - Chen JH
FAU - Chang, Wen-Chang
AU  - Chang WC
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120712
PL  - England
TA  - J Biomed Sci
JT  - Journal of biomedical science
JID - 9421567
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Reactive Oxygen Species)
SB  - IM
MH  - Animals
MH  - Autophagy/*genetics/physiology
MH  - Cell Death/*genetics/physiology
MH  - Cell Transformation, Neoplastic/metabolism
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - *Insulin Receptor Substrate Proteins/genetics/metabolism
MH  - Mice
MH  - NIH 3T3 Cells
MH  - *Neoplasms/metabolism/therapy
MH  - Oxidative Stress/genetics/physiology
MH  - Reactive Oxygen Species/*metabolism
MH  - Signal Transduction
PMC - PMC3430578
EDAT- 2012/07/14 06:00
MHDA- 2013/01/05 06:00
PMCR- 2012/07/12
CRDT- 2012/07/14 06:00
PHST- 2012/04/07 00:00 [received]
PHST- 2012/06/27 00:00 [accepted]
PHST- 2012/07/14 06:00 [entrez]
PHST- 2012/07/14 06:00 [pubmed]
PHST- 2013/01/05 06:00 [medline]
PHST- 2012/07/12 00:00 [pmc-release]
AID - 1423-0127-19-64 [pii]
AID - 10.1186/1423-0127-19-64 [doi]
PST - epublish
SO  - J Biomed Sci. 2012 Jul 12;19(1):64. doi: 10.1186/1423-0127-19-64.