title: UV Differentially Induces Oxidative Stress, DNA Damage and Apoptosis in BCR-ABL1-Positive Cells Sensitive and Resistant to Imatinib.
abstract: Chronic myeloid leukemia (CML) cells express the active BCR-ABL1 protein, which has been targeted by imatinib in CML therapy, but resistance to this drug is an emerging problem. BCR-ABL1 induces endogenous oxidative stress promoting genomic instability and imatinib resistance. In the present work, we investigated the extent of oxidative stress, DNA damage, apoptosis and expression of apoptosis-related genes in BCR-ABL1 cells sensitive and resistant to imatinib. The resistance resulted either from the Y253H mutation in the BCR-ABL1 gene or incubation in increasing concentrations of imatinib (AR). UV irradiation at a dose rate of 0.12 J/(m2 · s) induced more DNA damage detected by the T4 pyrimidine dimers glycosylase and hOGG1, recognizing oxidative modifications to DNA bases in imatinib-resistant than -sensitive cells. The resistant cells displayed also higher susceptibility to UV-induced apoptosis. These cells had lower native mitochondrial membrane potential than imatinib-sensitive cells, but UV-irradiation reversed that relationship. We observed a significant lowering of the expression of the succinate dehydrogenase (SDHB) gene, encoding a component of the complex II of the mitochondrial respiratory chain, which is involved in apoptosis sensing. Although detailed mechanism of imatinib resistance in AR cells in unknown, we detected the presence of the Y253H mutation in a fraction of these cells. In conclusion, imatinib-resistant cells may display a different extent of genome instability than their imatinib-sensitive counterparts, which may follow their different reactions to both endogenous and exogenous DNA-damaging factors, including DNA repair and apoptosis.
authors.affiliation: Department of Molecular Genetics, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland. ewelinas@biol.uni.lodz.pl.
authors.forename: Ewelina
authors.initials: E
authors.lastname: Synowiec
authors.affiliation: Department of Clinical Cytobiology, Medical Center for Postgraduate Education, Marymoncka 99, 01-813 Warsaw, Poland. graho@cmkp.edu.pl.
authors.forename: Grazyna
authors.initials: G
authors.lastname: Hoser
authors.affiliation: Department of Molecular Genetics, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland. katarzyny.wojcik@gmail.com.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Wojcik
authors.affiliation: Department of Orthodontics, Medical University of Lodz, Pomorska 251, 92-216 Lodz, Poland. elzbieta.pawlowska@umed.lodz.pl.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Pawlowska
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, Temple University, Philadelphia, PA 19140, USA. tskorski@temple.edu.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Skorski
authors.affiliation: Department of Molecular Genetics, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland. jblasiak@biol.uni.lodz.pl.
authors.forename: Janusz
authors.initials: J
authors.lastname: Błasiak
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D019008:Drug Resistance, Neoplasm / Q000528:radiation effects*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000528:radiation effects; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects / Q000528:radiation effects; D017354:Point Mutation; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays
chemical_list: D000970:Antineoplastic Agents; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl
keywords: BCR-ABL1; DNA damage; apoptosis; imatinib resistance; reactive oxygen species