Essential role of mitochondrial Stat3 in p38MAPK mediated apoptosis under oxidative stress

Abstract

Stat3 is an oncogene, frequently associated with malignant transformation. A body of evidence implicates that phospho-Stat3Y705 contributes to its nucleic translocation, while phospho-Stat3S727 leads to the accumulation in mitochondria. Both are of importance for tumor cell proliferation. In comparison to well-characterized signaling pathways interplaying with Stat3Y705, little is known about Stat3S727. In this work, we studied the influence of Stat3 deficiency on the viability of cells exposed to H2O2 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 Stat3Y705F, but not Stat3S727D, suggesting the importance of functional mitochondrial Stat3 in this context. We also found that ROS-mediated activation of ASK1/p38MAPK was involved and adding antioxidants, p38MAPK inhibitor, or genetic repression of ASK1 could easily rescue the cellular damage. Our finding reveals a new role of mitochondrial Stat3 in preventing ASK1/p38MAPK-mediated apoptosis, wich further support the notion that selective inhibition mitochondrial Stat3 could provide a primsing target for chemotherapy.

AIBP protects retinal ganglion cells against neuroinflammation and mitochondrial dysfunction in glaucomatous neurodegeneration

“…Our study demonstrated that loss of AIBP persistently increased phosphorylation of p38 and ERK1/2 in the retina. p38 is phosphorylated in response to cytokines and oxidative stress [ 79 , 80 ] and activation of the p38 signaling pathway leads to mitochondrial dysfunction and inflammatory responses [ [81] , [82] , [83] , [84] ]. Because a p38 inhibitor blocks mitochondrial dysfunction and inhibits cytochrome c release [ 85 ], it is likely that retinal AIBP not only plays a role in the stabilization of mitochondrial proteins, but also inhibits stress-activated intracellular signaling responses, such as p38 activation.…”

A trimethoxy flavonoid isolated from stem extract of Tabebuia chrysantha suppresses angiogenesis in angiosarcoma

“…[ 49,50 ] Also, researchers expressed there was a possibility that generated ROS and RNS/NO in tumour cells regulate MMP9 expression and/or activation. [ 51–53 ] Flavonoids/flavones are direct scavengers of ROS and RNS. [ 54 ] Henceforth, it was believed that TMF as a flavone scavenged ROS and RNS free radicals and thereby suppress activation of both STAT3 and MMP9.…”

Physiological regulation of reactive oxygen species in organisms based on their physicochemical properties

“…MAPKs are recognized as key regulatory proteins in oxidative signal transduction. Under physiological conditions, ROS regulate the activity of MAPK to transmit oxidation signals by targeting MAPK phosphatases, members of the PTP family . However, excessive ROS will activate protein phosphatases, causing dysfunction of oxidative signal transduction and exciting the oxidative stress response.…”