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Preprint
Redox Regulation of Cell Migration via Nischarin S-glutathionylation
bioRxiv
26 Sep 2025
PMID: 41040280
Abstract
Reactive oxygen species (ROS) are central players in redox signaling, controlling all biological processes in human health. Many reports demonstrated that ROS play essential roles in regulating cell migration and invasion, while contributing to cancer progression and metastasis, potentially via inducing protein cysteine oxidations. Nevertheless, specific redox players involved in cell migration and invasion remain ill-defined. In this report, we found that Nischarin (NISCH), established as a tumor suppressor, is susceptible to S-glutathionylation, selectively at Cys185 located near its leucine-rich repeat (LRR) domains, which are implicated in protein-protein interactions with Rac1 and PAK1. We demonstrated that epithelial breast cancer cell lines, MCF7 and MDA-MB-231, expressing NISCH wild-type (WT), compared to its cysteine mutant (C185S), exhibit increased migration and invasion in response to oxidative stress, such as limited glucose. Mechanistically, NISCH S-glutathionylation reduced its binding to Rac1 and PAK1, without altering its binding to integrin α5. The dissociation of NISCH led to the activation of Rac1 and PAK1, resulting in the localization of Rac1 to the cell periphery, which facilitates lamellipodia formation. The activated PAK1 increased the phosphorylation of the LIMK1-cofilin axis, thereby further enhancing actin filament dynamics that promote cell migration. Based on the mechanistic analysis, we produced an engineered NISCH construct, composed of the N-terminal PX and LRR domains. We demonstrated that the engineered NISCH PX-LRR constructs, particularly one lacking the S-glutathionylation site (i.e., C185S), can suppress the migration, invasion, and colony formation of MDA-MB-231 cells, regardless of the presence of oxidative stress. Our data reports a new redox player in cell migration and invasion, while supporting the potential application of NISCH-derived protein-based therapeutics for breast cancer.
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Details
- Title
- Redox Regulation of Cell Migration via Nischarin S-glutathionylation
- Creators
- Madhu C Shivamadhu - Drexel University, ChemistryDhanushika S K Kukulage - Drexel University, ChemistryRayavarapu Padmavathi - Drexel University, ChemistryDaniel Oppong - Drexel University, ChemistryFaezeh Mashhadi Ramezani - Drexel University, ChemistryDenaye N Eldershaw - The University of QueenslandBrett M Collins - The University of QueenslandYoung-Hoon Ahn - Drexel University, Chemistry
- Publication Details
- bioRxiv
- Publisher
- United States
- Grant note
- R01 GM143214 / NIGMS NIH HHS
- Resource Type
- Preprint
- Language
- English
- Academic Unit
- Chemistry
- Other Identifier
- 991022121059504721