Modulation of Gene Expression and Tumor Cell Growth by Redox Modification of STAT3

Reactive oxygen species (ROS) promote tumor cell proliferation and survival by directly modulating growth-regulatory molecules and key transcription factors. The signal transducer and activator of transcription 3 ( STAT3) is constitutively active in a variety of tumor cell types, where the effect of ROS on the Janus kinase/STAT pathway has been examined. We report here that STAT3is directly sensitive to intracellular oxidants. Oxidation of conserved cysteines by peroxide decreased STAT3binding to consensus serum-inducible elements (SIE) in vitro and in vivo and diminished interleukin (IL)-6–mediated reporter expression. Inhibitory effects produced by cysteine oxidation in STAT3were negated in redox-insensitive STAT3mutants. In contrast, ROS had no effect on IL-6–induced STAT3recruitment to the c- myc P2 promoter. Expression of a redox-insensitive STAT3in breast carcinoma cells accelerated their proliferation while reducing resistance to oxidative stress. Our results implicate STAT3in coupling intracellular redox homeostasis to cell proliferation and survival. Cancer Res; 70(20); 8222–32. ©2010 AACR.