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

Abstract

Reactive oxygen species (ROS) promote tumor cell proliferation and survival by directly modulating growthregulatory 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 STAT3 is directly sensitive to intracellular oxidants. Oxidation of conserved cysteines by peroxide decreased STAT3 binding 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 STAT3 were negated in redox-insensitive STAT3 mutants. In contrast, ROS had no effect on IL-6-induced STAT3 recruitment to the c-myc P2 promoter. Expression of a redoxinsensitive STAT3 in breast carcinoma cells accelerated their proliferation while reducing resistance to oxidative stress. Our results implicate STAT3 in coupling intracellular redox homeostasis to cell proliferation and survival. Cancer Res; 70(20); 8222-32. ©2010 AACR.

Novel Thiosemicarbazones Regulate the Signal Transducer and Activator of Transcription 3 (STAT3) Pathway: Inhibition of Constitutive and Interleukin 6–Induced Activation by Iron Depletion

“…2), indicating that ROS generation is involved in mediating this effect. Interestingly, ROS can inhibit STAT3 signaling by oxidation of conserved cysteines on JAK and STAT proteins that decrease their activation, implicating STAT3 as a mediator of redox homeostasis (Mamoon et al, 2007;Li et al, 2010). More recently, STAT3 transcriptional activity has been shown to be directly regulated by the redox function of the APE1/Ref-1 endonuclease (Cardoso et al, 2012).…”

A Resveratrol Analogue Promotes ERKMAPK–Dependent Stat3 Serine and Tyrosine Phosphorylation Alterations and Antitumor Effects In Vitro against Human Tumor Cells

“…It is notable that Cmpd1 lacks the side chain hydroxyl groups that are known to drive the antioxidant properties and the oxidative stress/redox mechanisms of resveratrol and pterostilbene, mechanisms known to promote biologic responses (Bhat et al, 2001;Rimando et al, 2002;Pan et al, 2008;Farghali et al, 2013;McCormack and McFadden, 2013), although we show that the 49 acetoxy group becomes hydrolyzed inside tumor cells. Although Stat3 signaling has been reported to be influenced by redox changes (Li et al, 2010;Liu et al, 2012), whether Cmpd1 induces oxidative stress events that contribute to the inhibition of Stat3 activation and the induction of antitumor responses in vitro is unknown. The inhibitory activity of Cmpd1 against the Stat3 pathway suggests the potential that this agent could be useful as part of treatment strategies tailored to tumors harboring aberrantly active Stat3 following in vivo validation of antitumor efficacy in Stat3 relevant tumor models.…”

BGB-283, a Novel RAF Kinase and EGFR Inhibitor, Displays Potent Antitumor Activity in BRAF-Mutated Colorectal Cancers

“…For in vitro studies, cells were harvested after 1 hour treatment at 37 C and lysed immediately as previously described (24). For in vivo studies, tumors were harvested at the indicated time points, snap-frozen in liquid nitrogen, and stored at À80 C. Tumors were homogenized in 500 mL lysis buffer in MP homogenization unit (Fast prep-24; MP bio, Cat.…”