期刊
PLOS ONE
卷 6, 期 12, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0029073
关键词
-
资金
- Flight Attendant Medical Research Institutes (FAMRI)
- National Institutes of Health [U54CA141868, CTSA UL RR 025005, RHL096931]
Background: Valosin-containing protein (VCP)/p97 is an AAA ATPase molecular chaperone that regulates vital cellular functions and protein-processing. A recent study indicated that VCP expression levels are correlated with prognosis and progression of non-small cell lung carcinoma (NSCLC). We not only verified these findings but also identified the specific role of VCP in NSCLC pathogenesis and progression. Methodology/Principal Findings: Our results show that VCP is significantly overexpressed in non-small cell lung carcinoma (NSCLC) as compared to normal tissues and cell lines (p < 0.001). Moreover, we observed the corresponding accumulation of ubiquitinated-proteins in NSCLC cell lines and tissues as compared to the normal controls. VCP inhibition by si/shRNA or small-molecule (Eeyarestatin I, EerI) significantly (p < 0.05, p < 0.00007) suppressed H1299 proliferation and migration but induced (p < 0.00001) apoptosis. Cell cycle analysis by flow cytometry verified this data and shows that VCP inhibition significantly (p < 0.001, p < 0.003) induced cell cycle arrest in the G0/G1 phases. We also found that VCP directly regulates p53 and NF kappa B protein levels as a potential mechanism to control tumor cell proliferation and progression. Finally, we evaluated the therapeutic potential of VCP inhibition and observed significantly reduced NSCLC tumor growth in both in vitro and xenograft murine (athymic-nude) models after EerI treatment (p, 0.05). Conclusions/Significance: Thus, targeting VCP in NSCLC may provide a novel strategy to restore p53 and NFkB levels and ameliorate the growth and tumorigenicity, leading to improved clinical outcomes.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据