SUPEROXIDE-MEDIATED ACTIVATION OF NF-kB SIGNALLING VIA REDOX-MEDIATED PP2A INACTIVATION

Abstract

Perturbation of cellular redox status and dysregulated redox signalling have recently emerged as hallmarks of cancer progression. While numerous studies reported elevated ROS levels in cancer cells, and they are shown to rely on a pro-oxidant milieu to survive, proliferate and metastasize, the underlying mechanism(s) in which ROS promotes tumourigenesis remains elusive. To that end, we examined the crosstalk between cellular redox metabolism and the activation of master transcription factor NF-ĸB. Here we demonstrated that a pro-oxidant condition of elevated superoxide levels induces IKK phosphorylation and NF-κB activity. We showed that sustained NF-κB signalling is a result of redox-inactivation of PP2A. Finally, we showed that modulation of intracellular redox milieu can influence the invasion and migration capabilities of less invasive breast cancer cells. Our work detailed the mechanistic insight of an oncogenic redox environment wherein NF-κB signalling is sustained via redox-inactivation of PP2A, and this increases invasiveness in breast cancer cells.