Nrf2 regulates cell motility through RhoA–ROCK1 signalling in non-small-cell lung cancer cells

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.

The Toxic Effect of Water-Soluble Particulate Pollutants from Biomass Burning on Alveolar Lung Cells

“…PWS did not change any of the cells' structural parameters. Related to the behavioral parameters, all three extract types decreased the migration and motility speed of cells at 250 µg/mL (Figure 5), in agreement with the decreased expression of Nrf2 [12] and its effect on cell migration [30].…”

“…Additionally, de Oliveira Alves et al [27] stated that biomass burning caused cell death by autophagy, apoptosis, and necrosis. Ko et al [30] observed that the suppression of Nrf2 in A549 cells inhibited cell migration and invasion, and shrunk cell size due to decreased focal adhesions via inhibition of the RhoA-ROCK1 pathway. In this study, the results show that water-soluble particle pollutants from biomass burning did not alter the area, optical volume, or eccentricity (how elongated the cells are) of cells for any of the three combustion types, a result that can also be observed by time-lapse microscopy (Figure 3).…”

Nrf2 modulates the hybrid epithelial/mesenchymal phenotype and Notch signaling during collective cancer migration

“…While Nrf2 has been widely studied in the context of antioxidant response and chemoresistance, [38][39][40][41] its function in cancer progression and invasion remains poorly understood. 3,18,[42][43][44] Our experimental-computational analysis revealed that the Nrf2-EMT-Notch network coordinates cancer cells near the leading edge during collective migration. In particular, Nrf2 acted as a PSF in suppressing a full EMT and promoting a hybrid E/M phenotype, in a spatially coordinated manner.…”

“…Previous studies report both positive and negative effects of Nrf2 on the collective invasion of various cancer cell types. 42,44,[48][49][50][51] In general, cancer cell migration can be influenced by multiple factors, such as leader cell formation, cell motility, and proliferation. In our experiment, the migration speed correlated with Dll4 expression and the formation of protruding tips and leader cells.…”

Nicotinic Acid Riboside Regulates Nrf-2/P62-Related Oxidative Stress and Autophagy to Attenuate Doxorubicin-Induced Cardiomyocyte Injury

“…As the downstream of Nrf-2, RhoA is a member of the Rho family of GTPases. Upon GTP binding, activated RhoA activates ROCK-1 [36]. ROCK-1 is known to play major roles in a wide range of cellular activities.…”