title: Valproic acid downregulates NF-κB p50 activity and IRAK-1 in a progressive thyroid carcinoma cell line.
abstract: Histone deacetylase inhibitor (HDACI) valproic acid (VPA) is a promising drug, currently in clinical phase 2, for the therapy of advanced/poorly differentiated thyroid cancer. The nuclear factor-κB (NF-κB) pathway is constitutively activated in most tumors, including thyroid carcinomas; this often contributes to aggressive tumor growth and therapeutic resistance. We hypothesized that VPA could be useful to decrease NF-κB activity in human thyroid cancer cells. To clarify this, we treated the highly progressive thyroid cancer cell line BHT-101 with VPA (1.0-3.0 mM) for 48 h. Real-time polymerase chain reaction (PCR) and Western blot were used to measure expression of NF-κB-regulatory genes and proteins. NF-κB p50 activity was measured using an ELISA-based colorimetric transcription factor assay kit. We found that VPA significantly and dose-dependently impaired NF-κB activity reducing DNA binding activity of NF-κB p50 subunit by 30% at 1 mM, 40% at 1.5 mM, and 70% at 3 mM. Expression of interleukin-1 receptor-associated kinase-1 (IRAK-1) protein, an upstream mediator of NF-κB activation, was reduced by ̴30% at 1 and 1.5 mM. Furthermore, 3 mM VPA treatment significantly decreased expressions of IRAK-1, phospho-IκBα and NF-κB p50 subunit protein by ̴ 50%. This is the first study to demonstrate that VPA decreases NF-κB activity in a progressive thyroid cancer cell line. Intriguingly, 1mM of VPA, a clinically safe dose in the therapeutic range for epilepsy, was sufficient to reduce NF-κB activity. Thus, VPA may be a promising agent to overcome chemoresistance in cancer therapy and to improve therapeutic efficiency.
authors: Institute of Pathology and Neuropathology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors: S
authors: S
authors: Schwertheim
authors: Institute of Pathology and Neuropathology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors: K
authors: K
authors: Worm
authors: Institute of Pathology and Neuropathology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors: K W
authors: KW
authors: Schmid
authors: Institute of Pathology and Neuropathology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors: S-Y
authors: SY
authors: Sheu-Grabellus
mesh_terms: D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D020672:I-kappa B Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D012333:RNA, Messenger; D000072000:NF-KappaB Inhibitor alpha; D014635:Valproic Acid; D053592:Interleukin-1 Receptor-Associated Kinases