Keap1 Inhibits Metastatic Properties of NSCLC Cells by Stabilizing Architectures of F-Actin and Focal Adhesions

Abstract

Low expression of the tumor suppressor Kelch-like ECH-associated protein 1 (KEAP1) in non-small cell lung cancer (NSCLC) often results in higher malignant biological behavior and poor prognosis; however, the underlying mechanism remains unclear. The present study demonstrates that overexpression of Keap1 significantly suppresses migration and invasion of three different lung cancer cells (A549, H460, and H1299). Highly expressed Keap1, compared with the control, promotes formation of multiple stress fibers with larger mature focal adhesion complexes in the cytoplasm where only fine focal adhesions were observed in the membrane under control conditions. RhoA activity significantly increased when Keap1 was overexpressed, whereas Myosin 9b expression was reduced but could be rescued by proteasome inhibition. Noticeably, mouse tumor xenografts with Keap1 overexpression were smaller in size and less metastatic relative to the control group. Taken together, these results demonstrate that Keap1 stabilizes F-actin cytoskeleton structures and inhibits focal adhesion turnover, thereby restraining the migration and invasion of NSCLC. Therefore, increasing Keap1 or targeting its downstream molecules might provide potential therapeutic benefits for the treatment of patients with NSCLC. This study provides mechanistic insight on the metastatic process in NSCLC and suggests that Keap1 and its downstream molecules may be valuable drug targets for NSCLC patients. .

Targeted substrate degradation by Kelch controls the actin cytoskeleton during ring canal expansion

“…Regulation of cytoskeletal structures by the ubiquitin-proteasome system is an emerging regulatory mechanism (Deng and Huang, 2014). However, most previous studies have used yeast or cultured cells (Wang et al, 2003;Chen et al, 2009;Razinia et al, 2011Razinia et al, , 2013Juanes and Piatti, 2016;Girouard et al, 2016;Wu et al, 2018). Our work is one of few examples to date detailing the mechanism by which the UPS organizes and remodels a cytoskeletal structure in a metazoan developmental model system.…”

Melittin from Apis florea Venom as a Promising Therapeutic Agent for Skin Cancer Treatment

“…It is well known that cancer cell motility is a fundamental ability and it is particularly important for its invasion and progressive stage, which requires the organization of actin cytoskeleton and migration of the signaling networks. It has also been reported that the cells that failed to reorganize the F-actin cytoskeleton and were enriched with stress fiber often displayed slower movements [ 32 , 33 , 34 ]. According to our previous results, a reduction of cell motility and the invasion of A375 cells were demonstrated when treatment was administered with Mel-AF (or Mel-AM).…”

“…Actin cytoskeleton is essentially involved in many cellular functions such as cell movement, proliferation, signaling system and apoptosis. It has been demonstrated that the suppression of cell motility was associated with actin stress, fiber forming and a reduction of actin reorganization [ 32 , 35 ]. Disruption of actin dynamics by F-actin stabilization also has been reported to facilitate apoptotic cell death via an increase in capase-3 activity [ 36 ].…”

Integrative omics analysis identifies subtypes with therapeutic implications in lung adenocarcinoma harboring KEAP1/NFE2L2

“…Only one alternative compound existed, which inhibited Rac signaling to mediate the actin cytoskeleton. Wu et al demonstrated that KEAP1 stabilized F-actin cytoskeleton structures and inhibited focal adhesion, thereby restraining migrations and invasions of lung cancers [34]. KEAP1/NFE2L2/CUL3 represented a mechanism of resistance to tyrosine kinase inhibitor in patients with EGFR-mutant nonsmall cell lung cancer [19].…”