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Mitochondrial localized Stat3 promotes breast cancer growth via phosphorylation of serine 727

Qifang Zhang1, Vidisha Raje, Vasily A Yakovlev

  • 1From the Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298.

The Journal of Biological Chemistry
|September 11, 2013
PubMed

Insights

Mitochondrial Signal transducer and activator of transcription 3 (Stat3) regulates breast cancer growth and reactive oxygen species (ROS) production. Serine 727 phosphorylation is critical for these mitochondrial Stat3 functions.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Oncology

Background:

  • Signal transducer and activator of transcription 3 (Stat3) is a known cancer mediator, traditionally viewed as a nuclear transcription factor.
  • Recent evidence reveals a novel mitochondrial function for Stat3 (mitoStat3), impacting cellular respiration and transformation.

Purpose of the Study:

  • To investigate the role of mitoStat3, specifically the phosphorylation of serine 727, in breast cancer pathogenesis.
  • To elucidate the effects of mitoStat3 on tumor growth, electron transport chain (ETC) activity, and reactive oxygen species (ROS) production.

Main Methods:

  • Utilized 4T1 breast cancer cells, a model for metastatic tumors.
  • Engineered Stat3 with a mitochondrial localization sequence (MLS-Stat3), substituting serine 727 with alanine (S727A) or aspartate (S727D).
  • Assessed tumor growth, ETC complex I activity, and ROS accumulation under varying conditions.

Main Results:

  • MLS-Stat3(S727A) expression correlated with slower tumor growth, reduced ETC complex I activity, and increased ROS under hypoxia.
  • MLS-Stat3(S727D) expression led to enhanced tumor growth, increased ETC complex I activity, and decreased ROS production.
  • These modifications significantly impacted mitochondrial function and cellular ROS levels.

Conclusions:

  • Serine 727 of mitoStat3 plays a crucial role in regulating breast cancer progression.
  • mitoStat3 influences tumor growth and ROS concentrations via its interaction with the electron transport chain.
  • This study uncovers a novel mechanism of cancer regulation involving mitochondrial Stat3 activity.
Keywords:
CancerMitochondriaPhosphorylationReactive Oxygen Species (ROS)STAT3STAT3 Breast CancerSerine

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