Critical role of VCP/p97 in the pathogenesis and progression of non-small cell lung carcinoma.
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.


RESULTS
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 NFκB 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
Thus, targeting VCP in NSCLC may provide a novel strategy to restore p53 and NFκB levels and ameliorate the growth and tumorigenicity, leading to improved clinical outcomes.
Department of Pediatric Respiratory Sciences, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Christopher W
CW
Valle
Taehong
T
Min
Manish
M
Bodas
Steven
S
Mazur
Shahnaz
S
Begum
Danni
D
Tang
Neeraj
N
Vij
D000251:Adenosine Triphosphatases / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D005434:Flow Cytometry; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D000074405:Valosin Containing Protein; D023041:Xenograft Model Antitumor Assays
D018797:Cell Cycle Proteins; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse