title: Established and novel NF-κB inhibitors lead to downregulation of TLR3 and the proliferation and cytokine secretion in HNSCC.
abstract: The transcriptional activation of NF-κB signalling has been identified as a major pathway involved in inflammation and tumor aggressiveness in a number of human cancers. Here we identify the impact of miscellaneous known and so far unknown NF-κB inhibitors originating from different drug classes on the function and proliferation of HNSCC. In detail: HNSCC cell lines were exposed to Acetylsalicylic Acid (ASA), Celecoxib, Dexamethasone, Curcumin and EPs 7630. Our major interest was to detect upstream alterations in cell signalling after applying NF-κB inhibiting substances. The inhibition of NF-κB signalling leads to an upstream regulation of Toll-like-receptor 3 (TLR3), a predominant receptor driving cell expansion. We find a marked downregulation of TLR3 and IKK complex, documenting upstream responses to NF-κB inhibition by every agent tested. In a second step we further analyse proliferation, cytokine production and alterations in the expression of downstream proteins such as cyclin D1 and c-Myc. Our data demonstrate decreased proliferation in response to incubation with aforementioned agents. Modulation of TLR3 and NF-κB expression is accompanied by altered profiles of IL-6 and IL-8 which are relevant cytokines in HNSCC progression. Proto-oncogenes cyclin D1 and c-myc are downregulated by all substances. Apart from the interplay of cytokines and TLR3, we substantiated EPs 7630 as a new and natural NF-κB inhibitor.
authors: Department of Otorhinolaryngology, University Hospital of Schleswig-Holstein Campus Lübeck, 23538 Lübeck, Germany.
authors: Christian
authors: C
authors: Meyer
authors: Ralph
authors: R
authors: Pries
authors: Barbara
authors: B
authors: Wollenberg
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D056741:Cyclin D / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007012:Hypopharyngeal Neoplasms / Q000378:metabolism*; D051550:I-kappa B Kinase / Q000187:drug effects / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D056741:Cyclin D; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D016271:Proto-Oncogene Proteins c-myc; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D051550:I-kappa B Kinase