title: Disruption of the transforming growth factor-β pathway by tolfenamic acid via the ERK MAP kinase pathway.
abstract: Transforming growth factor-β (TGF-β) modulates diverse cell physiological processes and plays a complicated role in tumor development. It has been well established that TGF-β inhibits cell proliferation in normal and early stage carcinoma and facilitates tumor metastasis in late-stage carcinoma. Therefore, blocking TGF-β signaling in advanced stage carcinogenesis provides a potentially interesting chemotherapeutic strategy. We aimed to determine the effect of tolfenamic acid (TA) on TGF-β-induced protumorigenic activity. Here, we demonstrate that TA attenuates tumor-promoting effects of TGF-β in cancer cells. Further observation indicates TA blocks the TGF-β/Smad pathway, and this blockage is mainly attributed to the interference of TGF-β1-driven phosphorylation of Smad2/3. We also show that TA could exert this effect on cancer cell lines from several different origins and that TA is much better than other non-steroidal anti-inflammatory drugs with respect to inhibition of TGF-β1-induced Smad2 phosphorylation. Finally, extracellular signal-regulated kinase mitogen-activated protein kinase plays a role in TA-induced suppression of Smad2/3 phosphorylation and subsequent nuclear accumulation of Smad2/3 in response to TGF-β1. Our study provides a possible mechanism by which TA affects anticancer activity by inhibiting the TGF-β pathway and sheds light on the application of TA for cancer patients.
authors.affiliation: Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA and.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhang
authors.forename: Kyung-Won
authors.initials: KW
authors.lastname: Min
authors.forename: Jason
authors.initials: J
authors.lastname: Liggett
authors.forename: Seung Joon
authors.initials: SJ
authors.lastname: Baek
mesh_terms: D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
chemical_list: C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D062367:ortho-Aminobenzoates; C009500:tolfenamic acid; D048049:Extracellular Signal-Regulated MAP Kinases