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.
Highlights
A pool of the nuclear transcription factor Signal transducer and activator of transcription 3 (Stat3) in the mitochondria controls respiration and Ras transformation
Serine 727 Affects the Ability of MLS-Stat3 to Regulate Transformation in Vitro— it has been reported that mitoStat3 is required for transformation of mouse embryo fibroblasts (MEFs), nothing is known about the role of mitoStat3 in the tumorigenesis of transformed cancer cell lines
We chose to examine the effects of mitoStat3 in 4T1 cells because expression of Stat3 is required for these cells to form tumors in immunocompetent mice [22]. 4T1 cells mimic the effects of human disease in that morbidity is due to micrometastatic tumor cells that migrate to liver, brain, lung, etc. early during the growth of the primary tumor
Summary
A pool of the nuclear transcription factor Stat in the mitochondria (mitoStat3) controls respiration and Ras transformation. 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 mitoStat in breast cancer and suggest a novel role for mitoStat in regulation of ROS concentrations through its action on the ETC. In contrast to its actions in the nucleus, mitoStat3-mediated regulation of respiration and Ras transformation requires serine 727 but not tyrosine 705 or the SH2 or DNA binding domains of Stat. In contrast to its actions in the nucleus, mitoStat3-mediated regulation of respiration and Ras transformation requires serine 727 but not tyrosine 705 or the SH2 or DNA binding domains of Stat3 These studies suggest that there is a completely novel function of Stat governed by its presence in the mitochondria where it controls energy balance. Our results are consistent with the hypothesis that mitoStat mediates its actions through affecting cellular levels of ROS, which may be mediated by changes in complex I activity of the ETC
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