title: Sodium salicylate acts through direct inhibition of phosphoinositide 3-kinase-like kinases to modulate topoisomerase-mediated DNA damage responses.
abstract: Chemopreventive non-steroidal anti-inflammatory drugs (NSAIDs) exhibit diverse pharmacological and biological activities mainly through their inhibitory effect on cyclooxygenase (COX). However, COX-independent mechanisms involving kinase inhibition have been proposed to explain certain therapeutic effects of NSAIDs. Here, we explored the potential relationship between chemopreventive NSAIDs and DNA damage responses induced by treatment with topoisomerase-targeting drugs. (1) Sodium salicylate, a non-COX-selective NSAID, was shown to reduce DNA damage-induced RPA and p53 phosphorylation. (2) The formation of enzyme cleavable complexes by topoisomerase-targeting drugs was not affected in the presence of sodium salicylate. (3) The attenuating effect of NSAIDs on the DNA damage responses is COX-2-independent, since COX-2-selective inhibitors failed to inhibit DNA damage-induced phosphorylation of replication protein A (RPA) and p53. (4) This COX-2-independent attenuating effect was mediated through interference of neither nuclear factor kappa B nor extracellular signal-regulated kinase pathways. (5) The activation of ataxia telangiectasia mutated (ATM) kinase and DNA-dependent protein kinase (DNA-PK), two key signal transducers upstream of RPA and p53, was found to be significantly reduced with sodium salicylate treatment. (6) Most importantly, sodium salicylate and other NSAIDs directly inhibited kinase activity of ATM and DNA-PK. The extent of inhibition on the kinase activity also correlated with the degree of attenuation on the DNA damage responses. (7) Unexpectedly, sodium salicylate showed a p53-independent protection effect on topoisomerase-mediated cell killing. Together, our study provides evidence that NSAIDs exhibit a novel COX-independent modulating activity of NSAIDs on the DNA damage responses and it is through inhibition of phosphoinositide 3-kinase-like kinases.
authors.affiliation: Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Jia-Rong
authors.initials: JR
authors.lastname: Fan
authors.forename: Ting-Hsiang
authors.initials: TH
authors.lastname: Huang
authors.forename: Chen-Yu
authors.initials: CY
authors.lastname: Wen
authors.forename: Tang-Long
authors.initials: TL
authors.lastname: Shen
authors.forename: Tsai-Kun
authors.initials: TK
authors.lastname: Li
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins; D002166:Camptothecin / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects*; D026942:DNA Topoisomerases / Q000187:drug effects*; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004347:Drug Interactions; D045325:HCT116 Cells; D006801:Humans; D016328:NF-kappa B; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051716:Replication Protein A / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012980:Sodium Salicylate / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018797:Cell Cycle Proteins; D052246:Cyclooxygenase 2 Inhibitors; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D051716:Replication Protein A; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051747:DNA-Activated Protein Kinase; D017346:Protein Serine-Threonine Kinases; D026942:DNA Topoisomerases; D012980:Sodium Salicylate; D002166:Camptothecin