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Journal article
Redox Regulation of Cell Migration via Nischarin S-glutathionylation
Free radical biology & medicine, v 243, pp 16-28
Feb 2026
PMID: 41213437
Featured in Collection : Research Supported by Drexel Libraries' OA Programs
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 oxidative modifications. 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 UniversityDhanushika S K Kukulage - Drexel UniversityRayavarapu Padmavathi - Drexel UniversityDaniel Oppong - Drexel UniversityFaezeh Mashhadi Ramezani - Drexel UniversityDenaye N Eldershaw - The University of QueenslandBrett M Collins - The University of QueenslandYoung-Hoon Ahn (Corresponding Author) - Drexel University
- Publication Details
- Free radical biology & medicine, v 243, pp 16-28
- Publisher
- Elsevier
- Number of pages
- 13
- Grant note
- National Institutes of Health (NIH): R01 GM143214 National Health and Medical Research Council (NHMRC): APP2016410 Drexel University
The research was supported by the National Institutes of Health (NIH) (R01 GM143214) (Y.H.A), a National Health and Medical Research Council (NHMRC) Investigator Grant (APP2016410) (B.M.C), and a research fund from Drexel University (Y.H.A). We would like to thank all the Ahn group members for assisting in the experiments.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemistry
- Web of Science ID
- WOS:001620205500001
- Scopus ID
- 2-s2.0-105023860202
- Other Identifier
- 991022130633004721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Endocrinology & Metabolism