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

Abstract

Signal transducer and activator of transcription 3 (Stat3) is a key mediator in the development of many cancers. For 20 years, it has been assumed that Stat3 mediates its biological activities as a nuclear localized transcription factor activated by many cytokines. However, recent studies from this laboratory and others indicate that Stat3 has an independent function in the mitochondria (mitoStat3) where it controls the activity of the electron transport chain (ETC) and mediates Ras-induced transformation of mouse embryo fibroblasts. The actions of mitoStat3 in controlling respiration and Ras transformation are mediated by the phosphorylation state of serine 727. To address the role of mitoStat3 in the pathogenesis of cells that are transformed, we used 4T1 breast cancer cells, which form tumors that metastasize in immunocompetent mice. Substitution of Ser-727 for an alanine or aspartate in Stat3 that has a mitochondrial localization sequence, MLS-Stat3, has profound effects on tumor growth, complex I activity of the ETC, and accumulation of reactive oxygen species (ROS). Cells expressing MLS-Stat3(S727A) display slower tumor growth, decreased complex I activity of the ETC, and increased ROS accumulation under hypoxia compared with cells expressing MLS-Stat3. In contrast, cells expressing MLS-Stat3(S727D) show enhanced tumor growth and complex I activity and decreased production of ROS. These results highlight the importance of serine 727 of mitoStat3 in breast cancer and suggest a novel role for mitoStat3 in regulation of ROS concentrations through its action on the ETC.

• Authors: Qifang Zhang, Vidisha Raje, Vasily A Yakovlev, Adly Yacoub, Karol Szczepanek, Jeremy Meier, Marta Derecka, Qun Chen, Ying Hu, Jennifer Sisler, Hossein Hamed, Edward J Lesnefsky, Kristoffer Valerie, Paul Dent, Andrew C Larner
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 43 Pg. 31280-8 (Oct 25 2013) ISSN: 1083-351X [Electronic] United States
• PMID: 24019511 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Mitochondrial Proteins
• Neoplasm Proteins
• Reactive Oxygen Species
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Serine
• Electron Transport Complex I

Topics

• Amino Acid Substitution
• Animals
• Cell Line, Transformed
• Cell Line, Tumor
• Electron Transport Complex I (genetics, metabolism)
• Female
• Mammary Neoplasms, Animal (genetics, metabolism, pathology)
• Mice
• Mitochondria (genetics, metabolism)
• Mitochondrial Proteins (genetics, metabolism)
• Mutation, Missense
• Neoplasm Proteins (genetics, metabolism)
• Phosphorylation (genetics)
• Reactive Oxygen Species (metabolism)
• STAT3 Transcription Factor (genetics, metabolism)
• Serine (genetics, metabolism)