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Sulfiredoxin redox-sensitive interaction with S100A4 and non-muscle myosin IIA regulates cancer cell motility.

ABSTRACT: Sulfiredoxin (Srx) is a redox active protein that participates in the reduction of oxidized cysteine residues. Here we identify a novel function of Srx through its specific binding to S-glutathionylated S100A4 affecting its interaction with non-muscle myosin (NMIIA), thereby modulating the effect of S100A4 on NMIIA function and impacting cell adhesion and migration. Srx forms a complex with S100A4 (and has stronger affinity for S-glutathionylated S100A4), regulates its activity, and mediates redox regulation of the interaction of S100A4 with NMIIA. The consequence of this regulation is microfilament remodeling and altered cellular motility and adhesion. Srx-overexpressing cells had reduced levels of adhesion, decreased levels of Tyr(397)-phosphorylated focal adhesion kinase, and increased cell motility in wound healing assays. These results describe a novel redox-sensitive role for Srx in mediating complex protein interactions with plausible consequences for cancer cell motility.

SUBMITTER: Bowers RR

PROVIDER: S-EPMC3472422 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Sulfiredoxin redox-sensitive interaction with S100A4 and non-muscle myosin IIA regulates cancer cell motility.

Bowers Robert R RR Manevich Yefim Y Townsend Danyelle M DM Tew Kenneth D KD

Biochemistry 20120919 39

Sulfiredoxin (Srx) is a redox active protein that participates in the reduction of oxidized cysteine residues. Here we identify a novel function of Srx through its specific binding to S-glutathionylated S100A4 affecting its interaction with non-muscle myosin (NMIIA), thereby modulating the effect of S100A4 on NMIIA function and impacting cell adhesion and migration. Srx forms a complex with S100A4 (and has stronger affinity for S-glutathionylated S100A4), regulates its activity, and mediates red ...[more]

PMID: 22934964

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Project description:BackgroundGlioblastoma (GBM) is the most aggressive form of brain tumor and has vascular-rich features. The S100A4/non-muscle myosin IIA (NMIIA) axis contributes to aggressive phenotypes in a variety of human malignancies, but little is known about its involvement in GBM tumorigenesis. Herein, we examined the role of the S100A4/NMIIA axis during tumor progression and vasculogenesis in GBM.MethodsWe performed immunohistochemistry for S100A4, NMIIA, and two hypoxic markers, hypoxia-inducible factor-1α (HIF-1α) and carbonic anhydrase 9 (CA9), in samples from 94 GBM cases. The functional impact of S100A4 knockdown and hypoxia were also assessed using a GBM cell line.ResultsIn clinical GBM samples, overexpression of S100A4 and NMIIA was observed in both non-pseudopalisading (Ps) and Ps (-associated) perinecrotic lesions, consistent with stabilization of HIF-1α and CA9. CD34(+) microvascular densities (MVDs) and the interaction of S100A4 and NMIIA were significantly higher in non-Ps perinecrotic lesions compared to those in Ps perinecrotic areas. In non-Ps perinecrotic lesions, S100A4(+)/HIF-1α(-) GBM cells were recruited to the surface of preexisting host vessels in the vascular-rich areas. Elevated vascular endothelial growth factor A (VEGFA) mRNA expression was found in S100A4(+)/HIF-1α(+) GBM cells adjacent to the vascular-rich areas. In addition, GBM patients with high S100A4 protein expression had significantly worse OS and PFS than did patients with low S100A4 expression. Knockdown of S100A4 in the GBM cell line KS-1 decreased migration capability, concomitant with decreased Slug expression; the opposite effects were elicited by blebbistatin-dependent inhibition of NMIIA.ConclusionS100A4(+)/HIF-1α(-) GBM cells are recruited to (and migrate along) preexisting vessels through inhibition of NMIIA activity. This is likely stimulated by extracellular VEGF that is released by S100A4(+)/HIF-1α(+) tumor cells in non-Ps perinecrotic lesions. In turn, these events engender tumor progression via acceleration of pro-tumorigenic vascular functions. Video abstract.

Dataset Information

Sulfiredoxin redox-sensitive interaction with S100A4 and non-muscle myosin IIA regulates cancer cell motility.

Publications

Sulfiredoxin redox-sensitive interaction with S100A4 and non-muscle myosin IIA regulates cancer cell motility.

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