期刊
ONCOTARGET
卷 6, 期 19, 页码 17725-17737出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.3918
关键词
ER stress; p97; ERAD; EMT; migration; invasion; metastasis
资金
- James Graham Brown Cancer Center
- University of Louisville
- Kosair Pediatric Cancer Program
- Molecular Targets from NIH [COBRE 8P20GM103482-10]
- Lung Cancer Research Foundation
- Rounsavall Foundation
Valosin-containing protein (VCP), also called p97, is a AAA+ ATPase that has been shown to be involved in endoplasmic reticulum-associated protein degradation (ERAD), mitochondria quality control and vesicle transport. We and others have previously found that disruption of VCP is sufficient to cause endoplasmic reticulum (ER) stress. We observed that induction of ER stress either following siRNA mediated loss of VCP or inhibition of VCP with eeyarestatin I potently activates an EMT-like state in cells. Interestingly, both ER stress and EMT are reversible events. Further, brief treatment of cells with eeyarestatin I increases EMT markers, and migratory and invasive properties of lung cancer cells. By examining primary lung adenocarcinoma patient samples we find that the VCP locus is heterozygously lost in nearly half of lung adenocarcinomas and VCP protein expression is decreased in nearly all primary lung tumors. Further, primary lung adenocarcinomas have increased ER stress and EMT markers. These observations have potential clinical relevance because increased ER stress and EMT markers are known to contribute to chemoresistance and poor survival of patients with lung adenocarcinoma.
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