S100A4 inhibits cell proliferation by interfering with the RAGE V domain-S100A1

Yu, Chin; Khan, Imran A.; Yuan, Tai Yi; Chou, Ruey Hwang

doi:10.1101/391136

2018

DOI: 10.1101/391136

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S100A4 inhibits cell proliferation by interfering with the RAGE V domain-S100A1

Chin Yu

Imran A. Khan

Tai Yi Yuan

et al.

Abstract: The Ca 2+ -dependent human S100A4 (Mts1) protein is part of the S100 family, and the S100A1 protein is the target of S100A4. Here, we studied the interactions of S100A1 with S100A4 using nuclear magnetic resonance (NMR; 700 MHz) spectroscopy. We used HADDOCK software to model S100A4 and S100A1, and we observed that S100A1 and the RAGE V domain have an analogous binding area in S100A4. We discovered that S100A4 acts as an antagonist among the RAGE V domain and S100A1, which inhibits tumorigenesis and cell proli… Show more

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Cited by 2 publications

References 57 publications

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The Anti-Cancer Activity of Pentamidine and Its Derivatives (WLC-4059) Is through Blocking the Interaction between S100A1 and RAGE V Domain

et al. 2022

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The S100A1 protein in humans is a calcium-binding protein. Upon Ca2+ binding to S100A1 EF-hand motifs, the conformation of S100A1 changes and promotes interactions with target proteins. RAGE consists of three domains: the cytoplasmic, transmembrane, and extracellular domains. The extracellular domain consists of C1, C2, and V domains. V domains are the primary receptors for the S100 protein. It was reported several years ago that S100A1 and RAGE V domains interact in a pathway involving S100A1-RAGE signaling, whereby S100A1 binds to the V domain, resulting in RAGE dimerization. The autophosphorylation of the cytoplasmic domain initiates a signaling cascade that regulates cell proliferation, cell growth, and tumor formation. In this study, we used pentamidine and a newly synthesized pentamidine analog (WLC-4059) to inhibit the S100A1-RAGE V interaction. 1H-15N HSQC NMR titration was carried out to characterize the interaction between mS100A1 (mutant S100A1, C86S) and pentamidine analogs. We found that pentamidine analogs interact with S100A1 via 1H-15N HSQC NMR spectroscopy. Based on the results, we utilized the HADDOCK program to generate structures of the mS100A1–WLC-4059 binary complex. Interestingly, the binary complex overlapped with the complex crystal structure of the mS100A1–RAGE-V domain, proving that WLC-4059 blocks interaction sites between S100A1 and RAGE-V. A WST-1 cell proliferation assay also supported these results. We conclude that pentamidine analogs could potentially enhance therapeutic approaches against cancers.

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The Anti-Cancer Activity of Pentamidine and Its Derivatives (WLC-4059) Is through Blocking the Interaction between S100A1 and RAGE V Domain

et al. 2022

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RAGE Signaling in Melanoma Tumors

Olaoba

Kadasah

Vetter

et al. 2020

IJMS

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Despite recent progresses in its treatment, malignant cutaneous melanoma remains a cancer with very poor prognosis. Emerging evidences suggest that the receptor for advance glycation end products (RAGE) plays a key role in melanoma progression through its activation in both cancer and stromal cells. In tumors, RAGE activation is fueled by numerous ligands, S100B and HMGB1 being the most notable, but the role of many other ligands is not well understood and should not be underappreciated. Here, we provide a review of the current role of RAGE in melanoma and conclude that targeting RAGE in melanoma could be an approach to improve the outcomes of melanoma patients.

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S100A4 inhibits cell proliferation by interfering with the RAGE V domain-S100A1

Cited by 2 publications

References 57 publications

The Anti-Cancer Activity of Pentamidine and Its Derivatives (WLC-4059) Is through Blocking the Interaction between S100A1 and RAGE V Domain

The Anti-Cancer Activity of Pentamidine and Its Derivatives (WLC-4059) Is through Blocking the Interaction between S100A1 and RAGE V Domain

RAGE Signaling in Melanoma Tumors

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