Chronic arsenic exposure promotes cell migration via KEAP1-mediated F-actin cytoskeletal rearrangement.

Abstract

Chronic arsenic exposure is a known environmental risk factor for lung cancer, yet the mechanisms underlying arsenite-induced malignant transformation remain unclear. Kelch-like ECH-associated protein 1 (KEAP1) has been shown to directly bind to F-actin, suggesting its potential role in cytoskeletal organization and thus involvement of oncogenic phenotypes. In this study, chronic exposure to 0.1 μM arsenite for up to 36 weeks led to malignant transformation accompanied with a significant decrease in KEAP1 protein level and F-actin cytoskeletal rearrangement in human bronchial epithelial (BEAS-2B) cells. The actin polymerization inhibitor cytochalasin D attenuated arsenite-induced cell migration. Immunofluorescence showed limited spatial association between KEAP1 and the actin cytoskeleton. KEAP1 overexpression suppressed F-actin cytoskeletal rearrangement and arsenic-induced elevation of migratory capacity, while NRF2 knockout did not rescue F-actin cytoskeletal rearrangement in arsenite-transformed cells. These data suggest that arsenite induces the malignant transformation of BEAS-2B cells, and this process involves KEAP1- associated rearrangement of the F-actin cytoskeleton, highlighting a critical role of KEAP1 in cytoskeletal dynamics and cell migration during transformation. Moreover, the role of KEAP1 may be independent of the classical KEAP1-NRF2 axis.

Key Findings

• Chronic arsenic exposure leads to malignant transformation and decreased KEAP1 protein levels in human bronchial epithelial cells.
• KEAP1 mediates F-actin cytoskeletal rearrangement which promotes cell migration independent of NRF2 signaling.
• Overexpression of KEAP1 suppresses arsenic-induced cytoskeletal changes and migratory capacity, while NRF2 knockout does not reverse these effects.

Clinical Significance

Citation

Fang Xin, Wang Junyi, Yin Xianhanget al.. Chronic arsenic exposure promotes cell migration via KEAP1-mediated F-actin cytoskeletal rearrangement. Toxicology and applied pharmacology. 2026-Apr-10.