Loss of STAT3 in mouse embryonic fibroblasts reveals its Janus-like actions on mitochondrial function and cell viability

Zouein, Fouad A.; Duhé, Roy J.; Arany, István; Shirey, Kristin; Hosler, Jonathan P.; Liu, Huiling; Saad, Iman; Kurdi, Mazen

doi:10.1016/j.cyto.2013.12.006

Cited by 20 publications

(18 citation statements)

References 50 publications

(61 reference statements)

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“…This leads to increased Stat3-GRIM-19 interaction, which results in increased mitoStat3 translocation 26 , 56 . Increased ROS production by TNFα could be mediated by mitoStat3 26 , 56 , 57 . Similarly, increased ROS production by nerve growth factor (NGF) in PC12 cells has also been associated with increased Stat3 mitochondrial localization 29 .…”

Section: Regulation Of Mitochondrial Function By Mitochondrial Stamentioning

confidence: 99%

Mitochondrial Stat3, the Need for Design Thinking

Yang¹,

Rincón²

2016

Int. J. Biol. Sci.

121

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Stat3 has been studied extensively as a transcription factor, however the finding that Stat3 also localizes to mitochondria has opened a new area to discover non-classical functions. Here we review the current knowledge of mitochondrial Stat3 as a regulator of the electron transport chain (ETC) and its impact on mitochondrial production of ATP and ROS. We also describe recent findings identifying Stat3 as a regulator of mitochondrial Ca2+ homeostasis through its effect on the ETC. It is becoming evident that these non-classical functions of Stat3 can have a major impact on cancer progression, cardiovascular diseases, and inflammatory diseases. Therefore, mitochondrial Stat3 functions challenge the current design of therapies that solely target Stat3 as a transcription factor and suggest the need for “design thinking,” which leads to the development of novel strategies, to intervene the Stat3 pathway.

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Section: Regulation Of Mitochondrial Function By Mitochondrial Stamentioning

confidence: 99%

Mitochondrial Stat3, the Need for Design Thinking

Yang¹,

Rincón²

2016

Int. J. Biol. Sci.

121

View full text Add to dashboard Cite

show abstract

“…6). The findings from our lab and others suggest that STAT3 is important for mitochondrial function and cell viability by ensuring mitochondrial integrity and the expression of pro-survival genes (Park et al, 2014; Wegrzyn et al, 2009; Zouein et al, 2014). …”

Section: Discussionmentioning

confidence: 68%

Mitochondrial STAT3 is negatively regulated by SOCS3 and upregulated after spinal cord injury

Park

Lin

Benveniste

et al. 2016

Experimental Neurology

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Suppressor of cytokine signaling-3 (SOCS3) expression is induced by the Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) signaling pathway. SOCS3 then acts as a feedback inhibitor of JAK-STAT signaling. Previous studies have shown that knocking down SOCS3 in spinal cord neurons with Lentiviral delivery of SOCS3-targeting shRNA (shSOCS3) increased spinal cord injury (SCI)-induced tyrosine phosphorylation of STAT3 (P-STAT3 Tyr), which in part contributed to decreased neuronal death and demyelination as well as enhanced dendritic regeneration and protection of neuronal morphology after SCI. However, the role of serine phosphorylation of STAT3 (P-STAT3 Ser) is in large part undetermined. Our purposes of this study were to evaluate the expression patterns of P-STAT3 Ser and to explore the possible role of SOCS3 in the regulation of P-STAT3 Ser expression. Immunoblot analyses demonstrated that Oncostatin M (OSM), a member of the interleukin-6 (IL-6) cytokine family, induced both P-STAT3 Tyr and P-STAT3 Ser in SH-SY5Y cells. Subcellular fractionation further revealed that P-STAT3 Ser was localized in mitochondria. Overexpression of SOCS3 with a Lentivirus-mediated approach in SH-SY5Y cells inhibited OSM-induced P-STAT3 Ser in both cytosol and mitochondria fractions. In contrast, OSM-induced P-STAT3 Ser was further upregulated in both cytosol and mitochondria when SOCS3 was knocked down by Lentivirus-delivered shSOCS3. Using a rat T8 spinal cord complete transection model, we found that SCI induced upregulation of P-STAT3 Ser in the mitochondria of macrophages/microglia and neurons both rostral and caudal to the injury site of spinal cord. Collectively, these results suggest that SOCS3 regulation of STAT3 signaling plays critical roles in stress conditions.

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“…The reason why total STAT3 changed in paclitaxel-induced ESCC cells is probably associated with the feedback of ESCC cells to paclitaxel treatment as an integrated system. STAT3 was able to positively regulate the mitochondrial respiration in terminally differentiated cells (29,30) and mtSTAT3 increased the activity of complex I and II in the ETC in a transcriptional-independent manner (18). STAT3 was also linked to carcinogenesis and tumor development shown in previous studies (31)(32)(33).…”

Section: Discussionmentioning

confidence: 72%

Paclitaxel induces apoptosis of esophageal squamous cell carcinoma cells by downregulating STAT3 phosphorylation at Ser727

Zhang

et al. 2017

Oncology Reports

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Paclitaxel induces apoptosis in a variety of cancer cells. However, the mechanism of paclitaxel inducing apoptosis in human esophageal squamous cell carcinoma (ESCC) remains to be defined. In this study, we found that paclitaxel-induced apoptosis by increasing the relevant apoptosis protein expression and the release of cytochrome c via downregulation of signal transducer and activator of transcription 3 (STAT3) and phospho-STAT3 (Ser727). In addition, paclitaxel treatment of ESCC cells EC-1 and Eca-109 led to marked mitochondrial membrane potential depolarization and significantly increasing of reactive oxygen species. Moreover, paclitaxel treatment resulted in the inhibition of mitochondrial respiration. In conclusion, our findings reveal that paclitaxel induced apoptosis in both EC-1 and Eca-109 cells through the reduction of STAT3 and phospho‑STAT3 (Ser727) level, and suggest that paclitaxel may be of therapeutic potential in the treatment of ESCC through the induction of mitochondrial apoptosis in ESCC cells.

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Loss of STAT3 in mouse embryonic fibroblasts reveals its Janus-like actions on mitochondrial function and cell viability

Cited by 20 publications

References 50 publications

Mitochondrial Stat3, the Need for Design Thinking

Mitochondrial Stat3, the Need for Design Thinking

Mitochondrial STAT3 is negatively regulated by SOCS3 and upregulated after spinal cord injury

Paclitaxel induces apoptosis of esophageal squamous cell carcinoma cells by downregulating STAT3 phosphorylation at Ser727

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