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

SPECIFIC AIMSArachidonate 5-lipoxygenase (5-LO) is emerging as a key regulator of cancer cell proliferation and survival. The aim of this study was to elucidate the relationship between 5-LO expression/function and molecular events regulated by the tumor suppressor p53 in response to genotoxic stress. Our goal was to determine whether 5-LO could be involved in cancer chemoresistance.PRINCIPAL FINDINGS1. 5-LO expression and activity are up-regulated by genotoxic agentsGenotoxic agents, such as H2O2 (100 μM), etoposide (10 μM), and adriamycin (ADR, 250 ng/mL), as well as (TNF)α (50 ng/mL), but not Fas ligand (FasL, 100 ng/mL), induced a time-dependent expression of 5-LO protein in MPP89 mesothelioma cells (Fig. 1⤻ A) with a maximum reached at 16 h in the case of ADR (Fig. 1B⤻ ). This agent also stimulated 5-LO mRNA accumulation (Fig. 1C⤻ ), 5-LO translocation to the nuclear envelope (Fig. 1D⤻ ), and 5-HETE accumulation in conditioned medium (Fig. 1E⤻ ). ADR potently enhanced 5-LO protein expression in gliom...