title: The Fanconi anemia/BRCA pathway is involved in DNA interstrand cross-link repair of adriamycin-resistant leukemia cells.
abstract: The Fanconi anemia/BRCA (FA/BRCA) pathway plays a vital role in DNA damage repair induced by DNA cross-linking agents and is closely related to drug response in cancer treatment. Here we demonstrate that the FA/BRCA pathway contributes to acquired drug resistance in adriamycin (ADR)-resistant leukemia cell lines, and disruption of this pathway partially reverses the drug resistance. We observed that ADR-resistant cells have reduced DNA interstrand cross-links (ICL) compared with ADR-sensitive cells. Western blot studies demonstrated enhanced FA protein expression in ADR-resistant cells. Using siRNA to knock down FANCF in K562/R drug-resistant cells showed increases in sensitivity to ADR and ADR-induced DNA damage, and demonstrated a direct relationship between the FA/BRCA pathway and drug sensitivity. Overexpression of FANCF in K562 drug-sensitive cells partially reproduced the drug-resistant phenotype. These results show that the FA/BRCA pathway is involved in acquired ADR resistance of leukemia cells. The FA/BRCA pathway may be a new target to reverse ADR resistance in leukemia treatment.
authors.affiliation: Department of Hematology, The Third Xiangya Hospital of Central South University , Changsha, Hunan , China.
authors.forename: Chenjiao
authors.initials: C
authors.lastname: Yao
authors.forename: Wei
authors.initials: W
authors.lastname: Du
authors.forename: Haibing
authors.initials: H
authors.lastname: Chen
authors.forename: Sheng
authors.initials: S
authors.lastname: Xiao
authors.forename: Lihua
authors.initials: L
authors.lastname: Huang
authors.forename: Fangping
authors.initials: F
authors.lastname: Chen
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D052219:Fanconi Anemia Complementation Group F Protein / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D000903:Antibiotics, Antineoplastic; D019313:BRCA1 Protein; D024682:BRCA2 Protein; C499901:FANCF protein, human; D052219:Fanconi Anemia Complementation Group F Protein; D004317:Doxorubicin
keywords: DNA interstrand cross-link repair; FA/BRCA pathway; drug resistance; leukemia