Abstract C66: Impacts of ERK signaling on the regulation of antioxidant enzymes and ROS levels in human lung cancer cells exposed to lead acetate

Abstract

Abstract Lead compounds (Pb) are widespread environmental contaminants that have been evaluated as group 2A carcinogens. Recently, we showed that EGFR activation is an immediate response to Pb as a primary upstream molecule to initiate SFK and PKCα activation, and subsequently links to the Ras→Raf-1→MKK1/2→EKK signaling cascade. Also, activation of this signaling plays a defensive role against Pb genotoxicity. Here, we explore whether Pb disturbs the intracellular levels of antioxidant enzymes and reactive oxygen species (ROS), and whether ERK signaling modulates the oxidative stress elicited by Pb in CL3 human non-small-cell lung adenocarcinoma cells. We found that Pb lowered the protein levels of glutathione peroxidase-1 (GPX1) and catalase, yet it induced superoxide dismutase 2 (SOD2). The phenomena were reverted upon ERK inactivation or depletion. By contrast, forced expression of the MKK1/2→ERK signaling decreased GPX1 and catalase, but enhanced SOD2 protein levels. The activities of GPX1 and catalase, but not SOD2, were declined in Pb-treated cells, and blockage of ERK activation partially rescued the decreased GPX1 activity. On the other hand, Pb elevated intracellular ROS, and ERK inactivation further enhanced its levels. The antioxidant N-acetyl-cysteine markedly prevented the cytotoxicity of Pb during ERK inactivation. These results suggest that ERK activation could mediate in scavenging ROS toxicants following Pb; yet, this signaling also participates in down-regulation of GPX1 and catalase as well as up-regulation of SOD2 at the protein levels, which probably enhances the intracellular H2O2. Thus, ERK exhibits dual and opposing roles in modulating oxidative stress caused by Pb. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C66.