Please use this identifier to cite or link to this item: https://hdl.handle.net/11147/13322
Title: Interferon gamma-inducible NAMPT in melanoma cells serves as a mechanism of resistance to enhance tumor growth
Authors: Barba, Cindy
Ekiz, Hüseyin Atakan
Tang, William Weihao
Ghazaryan, Arevik
Hansen, Mason
Lee, Soh-Hyun
Voth, Warren Peter
Keywords: melanoma
NAMPT
interferon gamma
Nicotinamide Phosphoribosyltransferase
Metabolism
Expression
Nad(+)
Inhibitor
Pd-L1
Alpha
Beta
Issue Date: 2023
Publisher: MDPI
Abstract: Simple Summary The tumor microenvironment is complex, with interacting immune and tumor cells. Immune cells release inflammatory cytokines, including interferons (IFNs), that drive tumor clearance. However, evidence suggests that tumor cells can also utilize IFNs to enhance growth and survival in certain cases. We demonstrate that interferon gamma (IFN gamma) mediates the metabolic reprogramming of melanoma cells by inducing the essential NAD+ salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT) gene through STAT1 binding to the NAMPT locus. NAMPT is constitutively expressed in cells during normal homeostasis. However, melanoma cells have higher energetic demands and increased NAMPT. We show that IFN gamma signaling upregulates NAMPT in melanoma cells, increasing cell proliferation and survival. Further, STAT1-inducible Nampt promotes melanoma growth in mice. We provide evidence that melanoma cells directly respond to IFN gamma-activated STAT1 by increasing Nampt, which improves their fitness during tumor immunity. Elucidating mechanisms that regulate NAMPT expression can lead to enhanced therapeutic approaches with immunotherapies that utilize IFN signaling to improve patient outcomes. (1) Background: Immune cells infiltrate the tumor microenvironment and secrete inflammatory cytokines, including interferons (IFNs), to drive antitumor responses and promote tumor clearance. However, recent evidence suggests that sometimes, tumor cells can also harness IFNs to enhance growth and survival. The essential NAD+ salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT) gene is constitutively expressed in cells during normal homeostasis. However, melanoma cells have higher energetic demands and elevated NAMPT expression. We hypothesized that interferon gamma (IFN gamma) regulates NAMPT in tumor cells as a mechanism of resistance that impedes the normal anti-tumorigenic effects of IFN gamma. (2) Methods: Utilizing a variety of melanoma cells, mouse models, Crispr-Cas9, and molecular biology techniques, we explored the importance of IFN gamma-inducible NAMPT during melanoma growth. (3) Results: We demonstrated that IFN gamma mediates the metabolic reprogramming of melanoma cells by inducing Nampt through a Stat1 binding site in the Nampt gene, increasing cell proliferation and survival. Further, IFN/STAT1-inducible Nampt promotes melanoma in vivo. (4) Conclusions: We provided evidence that melanoma cells directly respond to IFN gamma by increasing NAMPT levels, improving their fitness and growth in vivo (control n = 36, SBS KO n = 46). This discovery unveils a possible therapeutic target that may improve the efficacy of immunotherapies involving IFN responses in the clinic.
URI: https://doi.org/10.3390/cancers15051411
https://hdl.handle.net/11147/13322
ISSN: 2072-6694
Appears in Collections:Molecular Biology and Genetics / Moleküler Biyoloji ve Genetik
PubMed İndeksli Yayınlar Koleksiyonu / PubMed Indexed Publications Collection
Scopus İndeksli Yayınlar Koleksiyonu / Scopus Indexed Publications Collection
WoS İndeksli Yayınlar Koleksiyonu / WoS Indexed Publications Collection

Files in This Item:
File SizeFormat 
13322.pdf2.28 MBAdobe PDFView/Open
Show full item record



CORE Recommender

SCOPUSTM   
Citations

1
checked on Mar 1, 2024

WEB OF SCIENCETM
Citations

1
checked on Mar 2, 2024

Page view(s)

34
checked on Feb 26, 2024

Download(s)

8
checked on Feb 26, 2024

Google ScholarTM

Check




Altmetric


Items in GCRIS Repository are protected by copyright, with all rights reserved, unless otherwise indicated.