MAP17 enhances the malignant behavior of tumor cells through ROS increase

Tumorigenesis occurs when the mechanisms involved in the controlof tissue homeostasis are disrupted and cells stop respondingto physiological signals. Therefore, genes capable of desensitizingtumoral cells from physiological signals may provide a selectiveadvantage within the tumoral mass and influence the outcomeof the disease. We undertook a large-scale genetic screen toidentify genes able to alter the cellular response to physiologicalsignals and provide selective advantage once tumorigenesis hasbegun. We identified MAP17, a small 17 kDa non-glycosylatedmembrane protein previously identified by differential displaybeing over-expressed in carcinomas. Tumor cells that over-expressMAP17 show an increased tumoral phenotype with enhanced proliferativecapabilities both in presence or absence of contact inhibition,decreased apoptotic sensitivity and increased migration. MAP17-expressingclones also grow better in nude mice. The increased malignantcell behavior induced by MAP17 are associated with an increasein reactive oxygen species (ROS) production, and the treatmentof MAP17-expressing cells with antioxidants results in a reductionin the tumorigenic properties of these cells. Treatment of melanomacells with inhibitors of Na⁺-coupled co-transporters lead toan inhibition of ROS increase and a decrease in the malignantcell behavior in MAP17-expressing clones. Finally, we show thatMAP17-dependent ROS increase and tumorigenesis are dependenton its PDZ-binding domain, since disruption of its sequenceby point mutations abolishes its ability to enhance ROS productionand tumorigenesis. Our work shows the tumorigenic capabilityof MAP17 through a connection between Na⁺-coupled co-transportersand ROS. Abbreviations: FBS, fetal bovine serum; DMEM, Dulbecco's modified Eagle's medium; PBS, phosphate-buffered saline; ROS, reactive oxygen species; MAP17, membrane associated protein 17 kDa Received March 27, 2007; revised May 8, 2007; accepted May 14, 2007.