5-lipoxygenase antagonizes genotoxic stress-induced apoptosis by altering p53 nuclear trafficking.
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.
Catalano
Alfonso
A
Department of Molecular Pathology and Innovative Therapies, Polytechnic University of Marche, Ancona, Italy. catgfp@yahoo.it
Caprari
Paola
P
Soddu
Silvia
S
Procopio
Antonio
A
Romano
Mario
M
D021581:Active Transport, Cell Nucleus; D017209:Apoptosis; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D022003:Cell Nucleus Structures / Q000737:chemistry; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009153:Mutagens / Q000633:toxicity*; D009363:Neoplasm Proteins / Q000032:analysis; D009369:Neoplasms / Q000737:chemistry / Q000201:enzymology* / Q000378:metabolism; D009687:Nuclear Proteins / Q000032:analysis; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors / Q000032:analysis; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
D009153:Mutagens; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D001094:Arachidonate 5-Lipoxygenase