Abstract
Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a key transcriptional regulator of several antioxidant and anti-inflammatory enzymes. It binds to its endogenous inhibitor Kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm under normal conditions. Various endogenous or environmental oxidative stresses can disrupt the Nrf2/Keap1 complex, allowing Nrf2 to translocate into the nucleus, where it induces the transcription of various cytoprotective enzymes by binding to antioxidant responsive elements. These enzymes have been reported to play a role in regulating tumour growth, angiogenesis, and chemoprevention. Invasion and migration are the most harmful aspects of cancer; they directly impacts the patients’ survival. Although the roles of Keap1/Nrf2 and their downstream genes in various cancers have been widely documented, their role in regulating cell motility still remains unclear, particularly in cancer cells. We observed that Nrf2 suppression following treatment with brusatol in non-small-cell lung cancer (NSCLC) cells with either exogenously introduced Keap1 or siNrf2 resulted in the inhibition of cell migration and invasion, with shrinking cell morphology due to decreased focal adhesions via inhibition of the RhoA–ROCK1 pathway. Nrf2 overexpression showed opposite results. Thus, the Nrf2/Keap1 pathway may affect cell motility by dysregulating the RhoA–ROCK1 signalling pathway in NSCLC.
Highlights
Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a key transcriptional regulator of several antioxidant and anti-inflammatory enzymes
We observed that the expression levels of epithelial to mesenchymal transition (EMT)-related molecules after suppression or overexpression of Nrf[2] varied depending on the cell lines irrespective of the presence of Nrf[2] (Fig. 3a,b). These results indicated that Nrf[2] regulates cell motility through the RhoA–ROCK1 pathway, and not through the EMT pathway
Brusatol-mediated inhibition of Nrf[2] induced down-regulation of the active RhoA-GTP form in the A549, but not in H460 cells (Fig. 4b), and overexpression of Nrf[2] by exogenously introducing Nrf[2] resulted in a rise in the RhoA-GTP levels in HCC827 cells (Fig. 4c). These findings suggest that Nrf[2] can regulate the RhoA–ROCK1 pathway through increased level of RhoA-GTP induced by the stability of RhoA and/or activity of RhoA-GTP in non-small-cell lung cancer (NSCLC) cells, which is associated with protein level of RhoA
Summary
Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a key transcriptional regulator of several antioxidant and anti-inflammatory enzymes It binds to its endogenous inhibitor Kelch-like ECHassociated protein 1 (Keap1) in the cytoplasm under normal conditions. Increasing number of studies have shown and continue to show that persistent Nrf[2] activation due to dysregulation of the Nrf2–Keap[1] pathway in various cancer cells induces cell proliferation/growth by reprogramming metabolic processes. This is associated with poor prognosis due to acquired resistance to chemotherapy[9,10]. In this study, we further investigated the mechanism underlying the induction of cell motility by the Nrf2–Keap[1] pathway in lung cancer cells
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