title: Defective p53 signaling in p53 wild-type tumors attenuates p21waf1 induction and cyclin B repression rendering them sensitive to Chk1 inhibitors that abrogate DNA damage-induced S and G2 arrest.
abstract: DNA damage induces cell cycle arrest to provide time for repair and enhance cell survival. The Chk1 inhibitor 7-hydroxystaurosporine (UCN-01) can overcome both S and G(2) arrest and drive cells through a lethal mitosis. S-phase arrest induced by the topoisomerase I inhibitor SN38 results from activation of Chk1 and degradation of Cdc25A phosphatase that occurs independent of p53 status. However, p53-mediated induction of p21(waf1) and repression of cyclin B prevent abrogation of S and G(2) arrest, respectively. Surprisingly, incubation of MCF10A immortalized breast cells with UCN-01 fails to elevate Cdc25A protein due to p53-mediated inhibition of Cdc25A transcription. Suppression of p21(waf1) in MCF10A cells overcame this transcriptional inhibition, and the S-phase-arrested cells became sensitive to UCN-01, although they now arrested in G(2) as cyclin B expression remained suppressed. We also compared the response of p53 wild-type tumors to the combination of SN38 and UCN-01. In CAKI-1, U87MG, and SUM102, SN38 induced p21(waf1) and the cells were resistant to UCN-01. In contrast, HCT116 and MCF7 cells had markedly attenuated induction of p21(waf1) and failed to repress cyclin B. Accordingly, these cells were susceptible to UCN-01-mediated abrogation of both S and G(2) arrest. SN38 induced expression of another p53-inducible gene, 14-3-3sigma, suggesting selective dysregulation of p53 response genes. In summary, several cell lines commonly considered wild-type for p53 appear to have defects in expression of selected p53 response genes following DNA damage, and this makes them sensitive to the combination of DNA damage plus Chk1 inhibitor.
authors.affiliation: Department of Pharmacology and Toxicology and Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH 03756, USA.
authors.forename: Aime A
authors.initials: AA
authors.lastname: Levesque
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Fanous
authors.forename: Alissa
authors.initials: A
authors.lastname: Poh
authors.forename: Alan
authors.initials: A
authors.lastname: Eastman
mesh_terms: D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D019926:Cyclin B / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology*; D016195:G2 Phase / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D000077146:Irinotecan; D009369:Neoplasms / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D016196:S Phase / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology
chemical_list: D019926:Cyclin B; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047428:Protein Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; D000077146:Irinotecan; C054852:7-hydroxystaurosporine; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D019311:Staurosporine; D002166:Camptothecin