ArticleClinical cancer research : an official journal of the American Association for Cancer Research2009
Nuclear NF-kappaB p65 phosphorylation at serine 276 by protein kinase A contributes to the malignant phenotype of head and neck cancer.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 72 citations in OpenAlex.
- Trial
- The roles and mechanisms of natural compounds in preventing and treating viral reproductive disorders in major economic livestock.Virulence · 2026Review
- PI3K-dependent GAB1/Erk phosphorylation renders head and neck squamous cell carcinoma sensitive to PI3Kα inhibitors.Cell death & disease · 2025Article
- Mutant PP2A Induces IGFBP2 Secretion to Promote Development of High-Grade Uterine Cancer.Cancer research · 2025Article
- Post-translational governance of NF-κB in cancer immunity: mechanisms and therapeutic horizons.Frontiers in immunology · 2025Review
- Post-translational modifications of p65: state of the art.Frontiers in cell and developmental biology · 2024Review
- Hypoxia-Mediated Complement 1q Binding Protein Regulates Metastasis and Chemoresistance in Triple-Negative Breast Cancer and Modulates the PKC-NF-κB-VCAM-1 Signaling Pathway.Frontiers in cell and developmental biology · 2021Article
- Review
- [Effects of farnesyltransferase silencing on the migration and invasion of tongue squamous cell carcinoma].Hua xi kou qiang yi xue za zhi = Huaxi kouqiang yixue zazhi = West China journal of stomatology · 2020Article
- Lactate Suppresses Macrophage Pro-Inflammatory Response to LPS Stimulation by Inhibition of YAP and NF-κB ActivationFrontiers in immunology · 2020Article
- Role of Inflammatory Markers in Prognosis of Oral Squamous Cell Carcinoma.Asian Pacific journal of cancer prevention : APJCP · 2019Article
- Metabolic Regulation of Glycolysis and AMP Activated Protein Kinase Pathways during Black Raspberry-Mediated Oral Cancer Chemoprevention.Metabolites · 2019Article
- Exclusive enteral nutrition protects against inflammatory bowel disease by inhibiting NF‑κB activation through regulation of the p38/MSK1 pathway.International journal of molecular medicine · 2018Article
- Microenvironmental regulation of the progression of oral potentially malignant disorders towards malignancy.Oncotarget · 2017Review
- Combination of EPA with Carotenoids and Polyphenol Synergistically Attenuated the Transformation of Microglia to M1 Phenotype Via Inhibition of NF-κB.Neuromolecular medicine · 2017Article
- Characterization of key transcription factors as molecular signatures of HPV-positive and HPV-negative oral cancers.Cancer medicine · 2017Article
- Virally delivered, constitutively active NFκB improves survival of injured retinal ganglion cells.The European journal of neuroscience · 2016Article
- Cross-talk between PKA-Cβ and p65 mediates synergistic induction of PDE4B by roflumilast and NTHi.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Article
- Inhibitors of NF-kappaB reverse cellular invasion and target gene upregulation in an experimental model of aggressive oral squamous cell carcinoma.Oral oncology · 2014Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
purposeAberrant nuclear activation and phosphorylation of the canonical NF-kappaB subunit RELA/p65 at Serine-536 by inhibitor kappaB kinase is prevalent in head and neck squamous cell carcinoma (HNSCC), but the role of other kinases in NF-kappaB activation has not been well defined. Here, we investigated the prevalence and function of p65-Ser276 phosphorylation by protein kinase A (PKA) in the malignant phenotype and gene transactivation, and studied p65-Ser276 as a potential target for therapy. EXPERIMENTAL
designPhospho and total p65 protein expression and localization were determined in HNSCC tissue array and in cell lines. The effects of the PKA inhibitor H-89 on NF-kappaB activation, downstream gene expression, cell proliferation and cell cycle were examined. Knockdown of PKA by specific siRNA confirmed the specificity.
resultsNF-kappaB p65 phosphorylated at Ser276 was prevalent in HNSCC and adjacent dysplastic mucosa, but localized to the cytoplasm in normal mucosa. In HNSCC lines, tumor necrosis factor-alpha (TNF-alpha) significantly increased, whereas H-89 inhibited constitutive and TNF-alpha-induced nuclear p65 (Ser276) phosphorylation, and significantly suppressed NF-kappaB and target gene IL-8 reporter activity. Knockdown of PKA by small interfering RNA inhibited NF-kappaB, IL-8, and BCL-XL reporter gene activities. H-89 suppressed cell proliferation, induced cell death, and blocked the cell cycle in G(1)-S phase. Consistent with its biological effects, H-89 down-modulated expression of NF-kappaB-related genes Cyclin D1, BCL2, BCL-XL, COX2, IL-8, and VEGF, as well as induced cell cycle inhibitor p21(CIP1/WAF1), while suppressing proliferative marker Ki67.
conclusionsNF-kappaB p65 (Ser276) phosphorylation by PKA promotes the malignant phenotype and holds potential as a therapeutic target in HNSCC.
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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.