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Modulation of gene expression and tumor cell growth by redox modification of STAT3

Li Li1, Shing-Hu Cheung, Emma L Evans

  • 1School of Biomedical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, United Kingdom.

Cancer Research
|September 3, 2010
PubMed

Insights

Reactive oxygen species (ROS) impact tumor growth by altering signal transducer and activator of transcription 3 (STAT3). Oxidizing STAT3 cysteine residues inhibits its DNA binding, affecting cell proliferation and survival.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Reactive oxygen species (ROS) are known to promote tumor cell proliferation and survival.
  • The signal transducer and activator of transcription 3 (STAT3) pathway is constitutively active in many cancer types.
  • Previous studies have explored the effects of ROS on the Janus kinase/STAT pathway.

Purpose of the Study:

  • To investigate the direct sensitivity of STAT3 to intracellular oxidants.
  • To determine how ROS-mediated oxidation of STAT3 affects its function and downstream signaling.
  • To elucidate the role of STAT3 in coupling cellular redox state to proliferation and survival.

Main Methods:

  • In vitro and in vivo experiments assessing STAT3 binding to serum-inducible elements (SIE) after peroxide treatment.
  • Reporter gene assays to measure interleukin (IL)-6-mediated gene expression.
  • Utilizing redox-insensitive STAT3 mutants to negate oxidation effects.
  • Expression of redox-insensitive STAT3 in breast carcinoma cells.

Main Results:

  • Oxidation of conserved cysteines in STAT3 by peroxide decreased its binding to SIE both in vitro and in vivo.
  • Interleukin (IL)-6-mediated reporter expression was diminished due to cysteine oxidation.
  • Inhibitory effects of cysteine oxidation were abolished in redox-insensitive STAT3 mutants.
  • ROS did not affect IL-6-induced STAT3 recruitment to the c-myc P2 promoter.
  • Expression of redox-insensitive STAT3 in breast cancer cells led to accelerated proliferation and reduced resistance to oxidative stress.

Conclusions:

  • STAT3 is directly sensitive to intracellular oxidants, with cysteine oxidation inhibiting its DNA-binding activity.
  • STAT3 plays a crucial role in linking intracellular redox homeostasis to cancer cell proliferation and survival.
  • Targeting STAT3's redox sensitivity could offer novel therapeutic strategies for cancer.

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