Epithelial-to-mesenchymal transition (EMT) promulgates epithelial cell associated disease-defining characteristics in
tumorigenesis and organ
fibrosis.
Growth factors such as
epidermal growth factor and
fibroblast growth factor in addition to
cytokines such as transforming growth factor-β1 (TGF-β1) is said to play a prominent role in remodeling related pathological events of
cancer progression such as invasion,
metastasis, apoptosis, EMT, etc. through redox related cellular secondary messengers, in particular the
reactive oxygen species (ROS). However, the signaling cascade underlying the redox mechanism and thereby the progression of EMT remains largely unknown. In this study, upon TGF-β1 treatment, we observed an induction in NOX isoforms-NOX2 and NOX4-that have time (early and late) and cellular localization (nucleus and autophagosome co-localized) dependent effects in mediating EMT associated cell proliferation and migration through activation of the
focal adhesion kinase (FAK)/SRC pathway in HeLa, human
cervical cancer cells. Upon silencing NOX2/4 gene expression and using the SRC inhibitor (
AZD0530), progression of TGF-β1 induced EMT related cellular remodeling, extra cellular matrix (ECM) production, cell migration and invasion, got significantly reverted. Together, these results indicate that NOX2 and NOX4 play important, albeit distinct, roles in the activation of
cytokine mediated EMT and its associated processes via
tyrosine phosphorylation of the FAK/SRC pathway.