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    The alternative reading frame tumor suppressor antagonizes hypoxia-induced cancer cell migration via interaction with the COOH-terminal binding protein corepressor

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    Authors
    Paliwal, Seema
    Kovi, Ramesh C.
    Nath, Bharath D.
    Chen, Ya-Wen
    Lewis, Brian C.
    Grossman, Steven R.
    UMass Chan Affiliations
    Program in Molecular Medicine
    Program in Gene Function and Expression
    Department of Medicine, Division of Gastroenterology
    Department of Medicine, Division of Hematology/Oncology
    Department of Cancer Biology
    Graduate School of Biomedical Sciences
    Document Type
    Journal Article
    Publication Date
    2007-10-03
    Keywords
    1-Phosphatidylinositol 3-Kinase; Cell Hypoxia; Cell Movement; Eye Proteins; *Genes, Tumor Suppressor; HCT116 Cells; Humans; Lung Neoplasms; NAD; Oxygen; *Reading Frames; Transfection
    Life Sciences
    Medicine and Health Sciences
    
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    Link to Full Text
    http://dx.doi.org/10.1158/0008-5472.CAN-07-1743
    Abstract
    The alternative reading frame (ARF) tumor suppressor exerts both p53-dependent and p53-independent activities critical to the prevention of cancer in mice and humans. Recent evidence from mouse models suggests that when p53 is absent, further loss of ARF can widen the tumor spectrum, and potentiate invasion and metastasis. A major target of the p53-independent activity of ARF is the COOH-terminal binding protein (CtBP) family of metabolically regulated transcriptional corepressors, which are degraded upon acute exposure to the ARF protein. CtBPs are activated under conditions of metabolic stress, such as hypoxia, to repress epithelial and proapoptotic genes, and can mediate hypoxia-induced migration of cancer cells. The possibility that ARF could suppress tumor cell migration as part of its p53-independent activities was thus explored. Small-interfering RNA (siRNA)-mediated knockdown of ARF in human lung carcinoma cells led to increased cell migration, especially during hypoxia, and this effect was blocked by concomitant treatment with CtBP2 siRNA. Introduction of ARF into p53 and ARF-null human colon cancer cells inhibited hypoxia-induced migration. Furthermore, overexpression of CtBP2 in ARF-expressing cells enhanced cell migration, and an ARF mutant defective in CtBP-family binding was impaired in its ability to inhibit cell migration induced by CtBP2. ARF depletion or CtBP2 overexpression was associated with decreased PTEN expression and activation of the phosphatidylinositol 3-kinase pathway, and a phosphatidylinositol 3-kinase inhibitor blocked CtBP2-mediated cell migration. Thus, ARF can suppress cell migration by antagonizing CtBP2 and the phosphatidylinositol 3-kinase pathway, and these data may explain the increased aggressiveness of ARF-null tumors in mouse models.
    Source
    Cancer Res. 2007 Oct 1;67(19):9322-9. Link to article on publisher's site
    DOI
    10.1158/0008-5472.CAN-07-1743
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/33714
    PubMed ID
    17909040
    Related Resources
    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1158/0008-5472.CAN-07-1743
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