title: Protein tyrosine phosphatase (PTP) inhibition enhances chromosomal stability after genotoxic stress: decreased chromosomal instability (CIN) at the expense of enhanced genomic instability (GIN)?
abstract: Inappropriate survival signaling after DNA damage may facilitate clonal expansion of genetically compromised cells, and it is known that protein tyrosine phosphatase (PTP) inhibitors activate key survival pathways. In this study we employed the genotoxicant, hexavalent chromium [Cr(VI)], which is a well-documented carcinogen of occupational and environmental concern. Cr(VI) induces a complex array of DNA damage, including DNA double strand breaks (DSBs). We recently reported that PTP inhibition bypassed cell cycle arrest and abrogated Cr(VI)-induced clonogenic lethality. Notably, PTP inhibition resulted in an increase in forward mutations at the HPRT locus, supporting the hypothesis that PTP inhibition in the presence of DNA damage may lead to genomic instability (GIN), via cell cycle checkpoint bypass. The aim of the present study was to determine the effect of PTP inhibition on DNA DSB formation and chromosomal integrity after Cr(VI) exposure. Diploid human lung fibroblasts were treated with Cr(VI) in the presence or absence of the PTP inhibitor, sodium orthovanadate, for up to 24h, and cells were analyzed for DNA DSBs and chromosomal damage. Cr(VI) treatment induced a rapid increase in DNA DSBs, and a significant increase in total chromosomal damage (chromatid breaks and gaps) after 24h. In sharp contrast, PTP inhibition abrogated both DNA DSBs and chromosomal damage after Cr(VI) treatment. In summary, PTP inhibition in the face of Cr(VI) genotoxic stress decreases chromosomal instability (CIN) but increases mutagenesis, which we postulate to be a result of error-prone DNA repair.
authors.affiliation: Department of Pharmacology and Physiology, The George Washington University Medical Center, 2300 I Street NW, Washington, DC 20037, United States.
authors.forename: Gina Chun
authors.initials: GC
authors.lastname: Kost
authors.forename: Steven R
authors.initials: SR
authors.lastname: Patierno
authors.forename: Sandra S
authors.initials: SS
authors.lastname: Wise
authors.forename: Amie L
authors.initials: AL
authors.lastname: Holmes
authors.forename: John Pierce
authors.initials: JP
authors.lastname: Wise
authors.forename: Susan
authors.initials: S
authors.lastname: Ceryak
mesh_terms: D002857:Chromium / Q000633:toxicity; D043171:Chromosomal Instability / Q000187:drug effects*; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D005347:Fibroblasts; D042822:Genomic Instability / Q000187:drug effects*; D006801:Humans; D008168:Lung / Q000166:cytology; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*
chemical_list: D002857:Chromium; D017027:Protein Tyrosine Phosphatases