Inhibition of Interferon-Gamma-Stimulated Melanoma Progression by Targeting Neuronal Nitric Oxide Synthase (nNOS)

Authors

Shirley Tong, Chapman University
Maris A. Cinelli, Northwestern University
Naglaa Salem El-Sayed, Chapman UniversityFollow
He Huang, Northwestern University
Anika Patel, Chapman University
Richard B. Silverman, Northwestern University
Sun Yang, Chapman UniversityFollow

Document Type

Article

Publication Date

2-1-2022

Abstract

Interferon-gamma (IFN-γ) is shown to stimulate melanoma development and progression. However, the underlying mechanism has not been completely defined. Our study aimed to determine the role of neuronal nitric oxide synthase (nNOS)-mediated signaling in IFN-γ-stimulated melanoma progression and the anti-melanoma effects of novel nNOS inhibitors. Our study shows that IFN-γ markedly induced the expression levels of nNOS in melanoma cells associated with increased intracellular nitric oxide (NO) levels. Co-treatment with novel nNOS inhibitors effectively alleviated IFN-γ-activated STAT1/3. Further, reverse phase protein array (RPPA) analysis demonstrated that IFN-γ induced the expression of HIF1α, c-Myc, and programmed death-ligand 1 (PD-L1), in contrast to IFN-α. Blocking the nNOS-mediated signaling pathway using nNOS-selective inhibitors was shown to effectively diminish IFN-γ-induced PD-L1 expression in melanoma cells. Using a human melanoma xenograft mouse model, the in vivo studies revealed that IFN-γ increased tumor growth compared to control, which was inhibited by the co-administration of nNOS inhibitor MAC-3-190. Another nNOS inhibitor, HH044, was shown to effectively inhibit in vivo tumor growth and was associated with reduced PD-L1 expression levels in melanoma xenografts. Our study demonstrates the important role of nNOS-mediated NO signaling in IFN-γ-stimulated melanoma progression. Targeting nNOS using highly selective small molecular inhibitors is a unique and effective strategy to improve melanoma treatment.

Comments

This article was originally published in Scientific Reports, volume 12, in 2022. https://doi.org/10.1038/s41598-022-05394-6

Recommended Citation

Tong, S., Cinelli, M.A., El-Sayed, N.S. et al. Inhibition of interferon‑gamma‑stimulated melanoma progression by targeting neuronal nitric oxide synthase (nNOS). Sci Rep. 2022;12:1701. https://doi.org/10.1038/s41598-022-05394-6

Copyright

The authors

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.