ArticleCancer research2014
Inducible nitric oxide synthase drives mTOR pathway activation and proliferation of human melanoma by reversible nitrosylation of TSC2.
Article in Cancer research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 69 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
69 citing papers in PubMed, 1 synthesis or guideline pooled it, 104 citations in OpenAlex.
- Prognostic Value of Inducible Nitric Oxide Synthase (iNOS) in Human Cancer: A Systematic Review and Meta-Analysis.BioMed research international · 2019Pooled it
- S-nitrosylation topology in melanoma: established mechanisms, unresolved redox-immune links, and a testable framework.Redox biology · 2026Review
- Nitric Oxide, Reactive Oxygen Species, and Focal Adhesion Kinase Mediate Anoikis Resistance in A375 and SK-MEL-28 Human Melanoma Cells.Antioxidants (Basel, Switzerland) · 2026Article
- Glutathione responsive iNOS inhibiting polymeric prodrug for targeted Inhibition of angiogenesis.Journal of nanobiotechnology · 2026Article
- S-nitrosylation of IRF7 induced by NOS1 expression in melanoma suppresses anti-tumor immunity.Cell death & disease · 2026Article
- S-Nitrosylation of p53 in Melanoma Cells Under Nitrosative Stress.International journal of molecular sciences · 2025Article
- Nitric oxide inhibits ten-eleven translocation DNA demethylases to regulate 5mC and 5hmC across the genome.Nature communications · 2025Article
- Development of a human colorectal carcinoma cell-based platform for studying inducible nitric oxide synthase expression and nitric oxide signaling dynamics.Frontiers in molecular biosciences · 2025Article
- NOS inhibition sensitizes metaplastic breast cancer to PI3K inhibition and taxane therapy via c-JUN repression.Nature communications · 2024Article
- Nitric oxide participates in sucrose-TOR signaling during meristem activation in Arabidopsis thaliana.Planta · 2024Article
- The murine metastatic microenvironment of experimental brain metastases of breast cancer differs by host age in vivo: a proteomic study.Clinical & experimental metastasis · 2024Article
- Nitric oxide inhibits ten-eleven translocation DNA demethylases to regulate 5mC and 5hmC across the genome.Research square · 2024Article
- A metabolic perspective on nitric oxide function in melanoma.Biochimica et biophysica acta. Reviews on cancer · 2024Review
- The Effects of Nitric Oxide on Choroidal Gene Expression.Journal of bioinformatics and systems biology : Open access · 2024Article
- The Role of Amino Acids in Non-Enzymatic Antioxidant Mechanisms in Cancer: A Review.Metabolites · 2023Review
- Nitric oxide inhibits FTO demethylase activity to regulate NRedox biology · 2023Article
- Use of cutting-edge RNA-sequencing technology to identify biomarkers and potential therapeutic targets in canine and feline cancers and other diseases.Journal of veterinary science · 2023Review
- Targeting Nitric Oxide: Say NO to Metastasis.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Review
- Uncoupled nitric oxide synthase activity promotes colorectal cancer progression.Frontiers in oncology · 2023Article
- Article
9 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 4 institutions in 3 countries.
Funding
Abstract
Melanoma is one of the cancers of fastest-rising incidence in the world. Inducible nitric oxide synthase (iNOS) is overexpressed in melanoma and other cancers, and previous data suggest that iNOS and nitric oxide (NO) drive survival and proliferation of human melanoma cells. However, specific mechanisms through which this occurs are poorly defined. One candidate is the PI3K-AKT-mTOR pathway, which plays a major role in proliferation, angiogenesis, and metastasis of melanoma and other cancers. We used the chick embryo chorioallantoic membrane (CAM) assay to test the hypothesis that melanoma growth is regulated by iNOS-dependent mTOR pathway activation. Both pharmacologic inhibition and siRNA-mediated gene silencing of iNOS suppressed melanoma proliferation and in vivo growth on the CAM in human melanoma models. This was associated with strong downregulation of mTOR pathway activation by Western blot analysis of p-mTOR, p70 ribosomal S6 kinase (p-P70S6K), p-S6RP, and p-4EBP1. iNOS expression and NO were associated with reversible nitrosylation of tuberous sclerosis complex (TSC) 2, and inhibited dimerization of TSC2 with its inhibitory partner TSC1, enhancing GTPase activity of its target Ras homolog enriched in brain (Rheb), a critical activator of mTOR signaling. Immunohistochemical analysis of tumor specimens from stage III melanoma patients showed a significant correlation between iNOS expression levels and expression of the mTOR pathway members. Exogenously supplied NO was also sufficient to reverse the mTOR pathway inhibition by the B-Raf inhibitor vemurafenib. In summary, covalent modification of TSC2 by iNOS-derived NO is associated with impaired TSC2/TSC1 dimerization, mTOR pathway activation, and proliferation of human melanoma. This model is consistent with the known association of iNOS overexpression and poor prognosis in melanoma and other cancers.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.