Essential role of mitochondrial Stat3 in p38 MAPK mediated apoptosis under oxidative stress

• Published in: Scientific reports 2017-11, Vol.7 (1), p.15388
• Main Authors: Cheng, Xinlai, Peuckert, Christiane, Wölfl, Stefan
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution; Apoptosis; HEK293 Cells; HeLa Cells; Humans; MAP Kinase Kinase Kinase 5 - genetics; MAP Kinase Kinase Kinase 5 - metabolism; MAP Kinase Signaling System; Mitochondria - genetics; Mitochondria - metabolism; Mitochondria - pathology; Mutation, Missense; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Oxidative Stress; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Reactive Oxygen Species - metabolism; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-15342-4

Stat3 is an oncogene, frequently associated with malignant transformation. A body of evidence implicates that phospho-Stat3 contributes to its nucleic translocation, while phospho-Stat3 leads to the accumulation in mitochondria. Both are of importance for tumor cell proliferation. In comparison to well-characterized signaling pathways interplaying with Stat3 , little is known about Stat3 . In this work, we studied the influence of Stat3 deficiency on the viability of cells exposed to H O or hypoxia using siRNA and CRISPR/Cas9 genome-editing. We found dysregulation of mitochondrial activity, which was associated with excessive ROS formation and reduced mitochondrial membrane potential, and observed a synergistic effect for oxidative stress-mediated apoptosis in Stat3-KD cells or cells carrying Stat3 , but not Stat3 , suggesting the importance of functional mitochondrial Stat3 in this context. We also found that ROS-mediated activation of ASK1/p38 was involved and adding antioxidants, p38 inhibitor, or genetic repression of ASK1 could easily rescue the cellular damage. Our finding reveals a new role of mitochondrial Stat3 in preventing ASK1/p38 -mediated apoptosis, wich further support the notion that selective inhibition mitochondrial Stat3 could provide a primsing target for chemotherapy.