Critical Role of VCP/p97 in the Pathogenesis and Progression of Non-Small Cell Lung Carcinoma

被引：77

作者：

Valle, Christopher W. ^{[1
]}

Min, Taehong ^{[1
]}

Bodas, Manish ^{[1
]}

Mazur, Steven ^{[1
]}

Begum, Shahnaz ^{[4
]}

Tang, Danni ^{[1
]}

Vij, Neeraj ^{[1
,2
,3
]}

机构：

[1] Johns Hopkins Sch Med, Dept Pediat Resp Sci, Baltimore, MD 21205 USA

[2] Johns Hopkins Sch Med, Johns Hopkins Phys Sci Oncol Ctr, Baltimore, MD USA

[3] Johns Hopkins Sch Med, Inst NanoBiotechnol, Baltimore, MD USA

[4] Johns Hopkins Sch Med, Dept Pathol, Baltimore, MD USA

来源：

PLOS ONE | 2011年 / 6卷 / 12期

基金：

美国国家卫生研究院;

关键词：

VALOSIN-CONTAINING PROTEIN; AAA ATPASE P97/VCP; KAPPA-B; SIGNALING PATHWAY; UBIQUITIN SYSTEM; EXPRESSION LEVEL; P97; PROGNOSIS; DEGRADATION; CANCER;

D O I：

10.1371/journal.pone.0029073

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：12

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