title: A mechanistic study of the proapoptotic effect of tolfenamic acid: involvement of NF-κB activation.
abstract: Recent studies demonstrate that tolfenamic acid (TA) induces apoptosis and suppresses the development and progression of several types of cancers. However, the underlying mechanisms are complex and remain to be fully elucidated. Nuclear factor-kappaB (NF-κB) plays a critical role in inflammation, cancer development and progression. Although non-steroidal anti-inflammatory drugs modulate NF-κB signaling pathway in different ways, the link between NF-κB and TA-induced apoptosis of colorectal cancer cells has yet to be thoroughly investigated. In this study, we examined the effects of TA on the NF-κB pathway and apoptosis. TA activated NF-κB transcriptional activity and binding affinity of NF-κB to DNA. TA-induced NF-κB activation was mediated by an increased phosphorylation and proteosomal degradation of IκB-α and subsequent p65 nuclear translocation. We also observed that TA stabilized p65 and increased nuclear accumulation via an increase of p65 phosphorylation at Ser276 residue, which was mediated by p38 mitogen-activated protein kinase and extracellular signal-regulated kinase. The knockout of p53 blocked TA-induced transcriptional activation of NF-κB, but not the p65 nuclear accumulation. TA increased transcriptional activity of p53 and the binding affinity of p53 with p65, which are mediated by p38 mitogen-activated protein kinase and extracellular signal-regulated kinase-stimulated Ser276 phosphorylation. TA-induced apoptosis was ameliorated by the knockout of p65 and p53 and the point mutation of p65 at Ser276 residue. We demonstrate a novel molecular mechanism by which TA induced the NF-κB and apoptosis in human colorectal cancer cells.
authors.affiliation: Department of Nutrition and Food Science, College of Agriculture and Natural Resources, University of Maryland, College Park, MD 20742, USA and.
authors.forename: Jin Boo
authors.initials: JB
authors.lastname: Jeong
authors.forename: Xuyu
authors.initials: X
authors.lastname: Yang
authors.forename: Ruth
authors.initials: R
authors.lastname: Clark
authors.forename: Jieun
authors.initials: J
authors.lastname: Choi
authors.forename: Seung Joon
authors.initials: SJ
authors.lastname: Baek
authors.forename: Seong-Ho
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000819:agonists* / Q000235:genetics; D010766:Phosphorylation; D064209:Phytochemicals / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport; D051996:Transcription Factor RelA / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D062367:ortho-Aminobenzoates / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D064209:Phytochemicals; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D062367:ortho-Aminobenzoates; D000072000:NF-KappaB Inhibitor alpha; C009500:tolfenamic acid; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases