266 - Alteration of Tumor Microenvironmental Redox State Inhibits Prostate Cancer Metastasis

Abstract

Cancer cells exhibit a plasticity of redox state so that the conversion between redox status in tumor microenvironment (TME) can be accomplished rapidly, thus, extracellular redox-related proteins may be a new potential therapeutic targets for metastasis. Cysteine(CyS)/glutamate transporter(xCT) and extracellular superoxide dismutase (ECSOD) are mainly TME-redox state hemeostasis regulator, one control redox coupling ratio CyS/Cystine(CySS), the latter control prooxidants level. Herein, we demonstrated xCT protein expression is significantly increased and correlated with high Gleason score PCa tissues. In contrast, ECSOD protein expression is significantly decreased in high Gleason score PCa tissues. A decrease in ECSOD may result in elevation of extracellular prooxidant levels due to the increase in O2●– and OONO●, while overexpression of xCT may result in imbalance of extracellular thiol couples. These changes in the extracellular redox state are likely to have a profound effect on activation of invasion-related proteins. Inhibition of extracellular O2●– by overexpression of ECSOD using adenovirus SOD3 transduction or altering extracellular Cys/CySS levels by knock-downed xCT protein expression using siRNA xCT resulted in inhibition of PCa cell invasion and decreased activity of MMP2. Simultaneously overexpressed ECSOD and knock-downed xCT inhibited PCa cell invasion greater than overexpressed ECSOD or knock-downed xCT alone (~70%, 50%, and 30%, respectively). In the co-culturing system, overexpressed ECSOD and knock-downed xCT in both PC3 and stromal cells (WPMY-1) decreased PCa cell invasion greater than overexpressed ECSOD and knock-downed xCT in only PC3 cells or stromal cells. In conclusion, our data indicated that synergic modulation of ECSOD and xCT expression would elevate the success of site- specific redox based therapies at TME. Since, paracrine signaling from stromal cells induce PCa cells to grow and metastatic, targeting ECSOD and xCT in both cancer and stromal cells would provide a greater inhibition of PCa metastasis.