title: The chloroethylating anticancer drug ACNU induces FRA1 that is involved in drug resistance of glioma cells.
abstract: FRA1 belongs, together with c-Fos and FosB, to the family of Fos proteins that form with members of the ATF and Jun family the transcription factor AP-1 (activator protein 1). Previously we showed that c-Fos protects mouse embryonic fibroblasts against the cytotoxic effects of ultraviolet (UV) light by induction of the endonuclease XPF, leading to enhanced nucleotide excision repair (NER) activity. Here, we analyzed the regulation of FRA1 in glioma cells treated with the anticancer drug nimustine (ACNU) and its role in ACNU-induced toxicity. We show that FRA1 is upregulated in glioblastoma cells following ACNU on mRNA and protein levels. Knockdown of FRA1 by either siRNA or shRNA clearly sensitized glioma cells towards ACNU-induced cell death. Despite decreased AP-1 binding activity upon FRA1 knockdown, this effect is independent on regulation of the AP-1 target genes fasL, ercc1 and xpf. In addition, FRA1 knockdown does not affect DNA repair capacity. However, lack of FRA1 attenuated the ACNU-induced phosphorylation of CHK1 and led to a reduced arrest of cells in G2/M and, thereby, presumably leads to enhanced cell death in the subsequent cell cycle.
authors.affiliation: Department of Toxicology, University Medical Center Mainz, Mainz, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Meise
authors.forename: Maja T
authors.initials: MT
authors.lastname: Tomicic
authors.forename: Bernd
authors.initials: B
authors.lastname: Kaina
authors.forename: Markus
authors.initials: M
authors.lastname: Christmann
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D053222:Fas Ligand Protein / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D020868:Gene Silencing / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D051379:Mice; D015376:Nimustine / Q000494:pharmacology / Q000627:therapeutic use*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D000099169:Fos-Related Antigen 1
chemical_list: D000970:Antineoplastic Agents; D053222:Fas Ligand Protein; D015376:Nimustine; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D000099169:Fos-Related Antigen 1