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5-Lipoxygenase antagonizes genotoxic stress-induced apoptosis by altering p53 nuclear trafficking

  1. Author:
    Catalano, A.
    Caprari, P.
    Soddu, S.
    Procopio, A.
    Romano, M.
  2. Author Address

    Univ Politecn Marche, Dipartimento Patol Mol & Terapie Innovat, I-60131 Ancona, Italy. Regina Elena Inst Canc Res, Mol Oncogenesis Lab, Rome, Italy. Gabriele DAnnunzio Univ Fdn, CeSI, Dept Biomed Sci, Chieti, Italy. Gabriele DAnnunzio Univ Fdn, CeSI, Aging Res Ctr, Chieti, Italy. NCI, Neural Dev Grp, Mouse Canc Genet Program, Frederick, MD 21701 USA Catalano, A, Univ Politecn Marche, Dipartimento Patol Mol & Terapie Innovat, Via Ranieri, I-60131 Ancona, Italy
    1. Year: 2004
    2. Date: SEP
  1. Journal: Faseb Journal
    1. 18
    2. 12
    3. Pages: Published online only
  2. Type of Article: Article
  1. Abstract:

    5-Lipoxygenase (5-LO) promotes cancer cell proliferation and survival by unclear mechanisms. Here, we show that 5-LO expression and activity were induced by genotoxic agents in a p53-independent manner and antagonized p53- or genotoxic drug-induced apoptosis in a variety of cancer cells. 5-LO inhibited p53- governed transactivation of the pro-apoptotic genes bax and pig3 but not of p21(WAF1/CIP1) or mdm2. This may be explained by 5-LO capability to inhibit the binding of p53 to promyelocytic leukemia protein (PML) and p53 subnuclear relocalization into PML-nuclear bodies in response to genotoxic stress. Interestingly, 5-LO activity appears to be involved in nuclear retention and inactivation of wild-type p53 in malignant mesothelioma cells. In these cells, genetic or pharmacological inhibition of 5-LO enabled suppression of in vitro tumorigenicity by low doses of chemotherapeutic drugs. Together, these results uncover novel functions of 5-LO and contribute to the understanding of 5-LO involvement in tumor progression. Moreover, they provide a rationale to the therapeutic use of 5-LO inhibitors to enhance cancer chemosensitivity in selected tumors

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External Sources

  1. WOS: 000224243200022

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