The functional role of a superoxide generating gene Nox1 in Ras oncogene-induced transformation and human tumor development

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The aim of our study is to elucidate the functional role of reactive oxygen species (ROS) -generating Nox1 family genes in development of human cancers by utilizing Ras-transformation as a model system and lay a foundation for treatment and diagnosis of human cancers. We previously found that Ras oncogene upregulates Nox1 expression via Raf-MEK-MAPK pathway and Nox1 generated-ROS are required for oncogenic Ras transformation. This implicates an important role as a new limiting factor for Nox1 in oncogenesis. In the current study, we demonstrated that Nox4-generated ROS confer cell survival activity to pancreatic cancer cells through the AKT-ASK1 pathway and inhibit cell growth of melanoma cells by deregulating cell cycle. Furthermore, we identified ER proteins, PDI family proteins as potential downstream targets for Nox1-generated ROS whose Cys-SH residues are selectively oxidized by ROS. In the future study, we will further analyze what activity associated with these redox proteins is essential for Nox1-mediated cell transformation process. Our discovery accelerates the dissection of Nox-redox signaling pathway and provides a novel insight into its functional role in cancer development.