title: Aspirin inhibits colon cancer cell and tumor growth and downregulates specificity protein (Sp) transcription factors.
abstract: Acetylsalicylic acid (aspirin) is highly effective for treating colon cancer patients postdiagnosis; however, the mechanisms of action of aspirin in colon cancer are not well defined. Aspirin and its major metabolite sodium salicylate induced apoptosis and decreased colon cancer cell growth and the sodium salt of aspirin also inhibited tumor growth in an athymic nude mouse xenograft model. Colon cancer cell growth inhibition was accompanied by downregulation of Sp1, Sp3 and Sp4 proteins and decreased expression of Sp-regulated gene products including bcl-2, survivin, VEGF, VEGFR1, cyclin D1, c-MET and p65 (NFκB). Moreover, we also showed by RNA interference that β-catenin, an important target of aspirin in some studies, is an Sp-regulated gene. Aspirin induced nuclear caspase-dependent cleavage of Sp1, Sp3 and Sp4 proteins and this response was related to sequestration of zinc ions since addition of zinc sulfate blocked aspirin-mediated apoptosis and repression of Sp proteins. The results demonstrate an important underlying mechanism of action of aspirin as an anticancer agent and, based on the rapid metabolism of aspirin to salicylate in humans and the high salicylate/aspirin ratios in serum, it is likely that the anticancer activity of aspirin is also due to the salicylate metabolite.
authors.affiliation: Department of Veterinary Physiology & Pharmacology, Texas A&M University, College Station, TX, USA.
authors.forename: Satya
authors.initials: S
authors.lastname: Pathi
authors.forename: Indira
authors.initials: I
authors.lastname: Jutooru
authors.forename: Gayathri
authors.initials: G
authors.lastname: Chadalapaka
authors.forename: Vijayalekshmi
authors.initials: V
authors.lastname: Nair
authors.forename: Syng-Ook
authors.initials: SO
authors.lastname: Lee
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
mesh_terms: D000818:Animals; D001241:Aspirin / Q000494:pharmacology / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D051703:Sp Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D051705:Sp3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D051706:Sp4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D051703:Sp Transcription Factors; D016329:Sp1 Transcription Factor; D051706:Sp4 Transcription Factor; D051705:Sp3 Transcription Factor; D001241:Aspirin