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RETRACTED: 5‐Lipoxygenase antagonizes genotoxic stress‐induced apoptosis by altering p53 nuclear trafficking
Author(s) -
Catalano Alfonso,
Caprari Paola,
Soddu Silvia,
Procopio Antonio,
Romano Mario
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-2258fje
Subject(s) - transactivation , cancer research , apoptosis , mdm2 , cancer cell , dna damage , chemistry , promyelocytic leukemia protein , in vitro , biology , cancer , nuclear protein , gene , gene expression , dna , transcription factor , biochemistry , genetics
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.