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

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          Abstract

          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 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/Significance

          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.

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          Most cited references38

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          Mdm2 promotes the rapid degradation of p53.

          Y Haupt, R Maya, A Kazaz … (1997)
          The p53 tumour-suppressor protein exerts antiproliferative effects, including growth arrest and apoptosis, in response to various types of stress. The activity of p53 is abrogated by mutations that occur frequently in tumours, as well as by several viral and cellular proteins. The Mdm2 oncoprotein is a potent inhibitor of p53. Mdm2 binds the transcriptional activation domain of p53 and blocks its ability to regulate target genes and to exert antiproliferative effects. On the other hand, p53 activates the expression of the mdm2 gene in an autoregulatory feedback loop. The interval between p53 activation and consequent Mdm2 accumulation defines a time window during which p53 exerts its effects. We now report that Mdm2 also promotes the rapid degradation of p53 under conditions in which p53 is otherwise stabilized. This effect of Mdm2 requires binding of p53; moreover, a small domain of p53, encompassing the Mdm2-binding site, confers Mdm2-dependent detstabilization upon heterologous proteins. Raised amounts of Mdm2 strongly repress mutant p53 accumulation in tumour-derived cells. During recovery from DNA damage, maximal Mdm2 induction coincides with rapid p53 loss. We propose that the Mdm2-promoted degradation of p53 provides a new mechanism to ensure effective termination of the p53 signal.
          Article 0 comments Cited 836 times – based on 0 reviews     Review now
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            Transcriptional control of human p53-regulated genes.

            Todd Riley, Eduardo D Sontag, Patricia Chen … (2008)
            The p53 protein regulates the transcription of many different genes in response to a wide variety of stress signals. Following DNA damage, p53 regulates key processes, including DNA repair, cell-cycle arrest, senescence and apoptosis, in order to suppress cancer. This Analysis article provides an overview of the current knowledge of p53-regulated genes in these pathways and others, and the mechanisms of their regulation. In addition, we present the most comprehensive list so far of human p53-regulated genes and their experimentally validated, functional binding sites that confer p53 regulation.
            Article 0 comments Cited 561 times – based on 0 reviews     Review now
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              Targeting the ubiquitin system in cancer therapy.

              Daniela Hoeller, Ivan Dikic (2009)
              The ubiquitin system is a network of proteins dedicated to the ubiquitylation of cellular targets and the subsequent control of numerous cellular functions. The deregulation of components of this elaborate network leads to human pathogenesis, including the development of many types of tumour. Alterations in the ubiquitin system that occur during the initiation and progression of cancer are now being uncovered, and this knowledge is starting to be exploited for both molecular diagnostics and the development of novel strategies to combat cancer.
              Article 0 comments Cited 211 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2011
                Publication date (Electronic): 22 December 2011
                Volume: 6
                Issue: 12
                Electronic Location Identifier: e29073
                Affiliations
                [1 ]Johns Hopkins Physical Sciences in Oncology Center, The Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
                [2 ]Department of Pediatric Respiratory Sciences, The Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
                [3 ]Institute of NanoBiotechnology, The Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
                [4 ]Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
                Virginia Commonwealth University, United States of America
                Author notes

                Conceived and designed the experiments: NV. Performed the experiments: CWV TM MB SM SB DT. Analyzed the data: NV CWV TM MB. Contributed reagents/materials/analysis tools: NV. Wrote the paper: CWV NV.

                Article
                Publisher ID: PONE-D-11-20457
                DOI: 10.1371/journal.pone.0029073
                PMC ID: 3245239
                PubMed ID: 22216170
                SO-VID: 69cc130b-7c19-4705-8b78-ff6ea415349c
                Copyright © Valle et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 17 October 2011
                Date accepted : 20 November 2011
                Page count
                Pages: 12
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Anatomy and Physiology
                Subject: Physiological Processes
                Subject: Respiratory System
                Subject: Biotechnology
                Subject: Drug Discovery
                Subject: Computational Biology
                Subject: Molecular Cell Biology
                Subject: Cell Growth
                Subject: Cellular Stress Responses
                Subject: Gene Expression
                Subject: Medicine
                Subject: Infectious Diseases
                Subject: Oncology
                Subject: Basic Cancer Research
                Subject: Metastasis
                Subject: Cancers and Neoplasms
                Subject: Lung and Intrathoracic Tumors
                Subject: Non-Small Cell Lung Cancer
                Subject: Pulmonology
                Subject: Environmental and Occupational Lung Diseases

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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