Abstract LB-28: Regulation of FOXM1 by NADPH oxidases in malignant mesothelioma cells

Abstract

Abstract Malignant mesothelioma (MM) is linked to the occupational exposure to asbestos with an estimated median survival of less than two years; effective therapy is lacking. Due to long latency periods, incidence is expected to rise in regions where asbestos use has been banned, as well as where worker protection is lacking. MM cells exhibit changes in oxidant and energy metabolism, with elevated expression of the NADPH oxidase NOX4. We hypothesize that NOX4 produces reactive oxygen species (ROS) that promote uncontrolled growth through redox-dependent signaling to core cell cycle factors such as FOXM1 and FOXO3a, transcription factors involved in responses in oxidative stress and cell cycle progression. Targeted microarrays were used to assess the expression levels of 96 genes involving redox metabolism in four human MM cell lines and one control mesothelial line (LP9) immortalized with hTERT. Gene expression profiles from MM cell lines indicate tumorigenesis commonly results in elevated expression of NOX activity and adaptation to constitutive production of ROS, including up-regulation of antioxidant enzymes and cytoprotective factors. mRNA for FOXM1, a transcription factor that regulates the G2/M transition in the cell cycle, was up-regulated in all four MM cell lines, and FOXM1 continued to be expressed in MM cells, but not LP9 cells, in the absence of growth factors. Inhibitors of NOX activity markedly reduced expression of FOXM1, which correlated with dose-dependent effects on MM cell proliferation and viability. In the HM MM cell line, thiostrepton (TS), a thiazole antibiotic that inhibits the expression of FOXM1 via an unknown mechanism, increased the rate of oxidation of DCF, hyper-activated ERK1/2, and showed dose-dependent effects on MM cell viability in vitro and MM tumor growth in Fox Chase SCID mice. N-acetyl-L-cysteine blocked activation of ERK1/2 and cell death by TS, indicating the cytotoxic effects of TS in MM cells may be dependent on induction of intolerable levels of oxidative stress. In support of this possibility, inhibitors of p38 MAPK accentuated the cytotoxic effects of TS on cell viability. Our studies indicate that altered oxidant metabolism that supports expression of cell cycle factors such as FOXM1 is a common property of MM cells, and suggest that either inhibiting or accentuating the production of ROS in MM cells may be useful therapeutic approaches in the treatment of MM. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-28.