title: Targeting the Fanconi anemia/BRCA pathway circumvents drug resistance in multiple myeloma.
abstract: The Fanconi anemia/BRCA (FA/BRCA) DNA damage repair pathway plays a pivotal role in the cellular response to replicative stress induced by DNA alkylating agents and greatly influences drug response in cancer treatment. We recently reported that FA/BRCA genes are overexpressed and causative for drug resistance in human melphalan-resistant multiple myeloma cell lines. However, the transcriptional regulation of the FA/BRCA pathway is not understood. In this report, we describe for the first time a novel function of the NF-kappaB subunits, RelB/p50, as transcriptional activators of the FA/BRCA pathway. Specifically, our findings point to constitutive phosphorylation of IkappaB kinase alpha and subsequent alterations in FANCD2 expression and function as underlying events leading to melphalan resistance in repeatedly exposed multiple myeloma cells. Inhibiting NF-kappaB by small interfering RNA, blocking the IkappaB kinase complex with BMS-345541, or using the proteasome inhibitor bortezomib drastically reduced FA/BRCA gene expression and FANCD2 protein expression in myeloma cells, resulting in diminished DNA damage repair and enhanced melphalan sensitivity. Importantly, we also found that bortezomib decreases FA/BRCA gene expression in multiple myeloma patients. These results show for the first time that NF-kappaB transcriptionally regulates the FA/BRCA pathway and provide evidence for targeting Fanconi anemia-mediated DNA repair to enhance chemotherapeutic response and circumvent drug resistance in myeloma patients.
authors.affiliation: Cancer Biology Ph.D. Program, University of South Florida, Tampa, Florida 33612, USA.
authors.forename: Danielle N
authors.initials: DN
authors.lastname: Yarde
authors.forename: Vasco
authors.initials: V
authors.lastname: Oliveira
authors.forename: Linda
authors.initials: L
authors.lastname: Mathews
authors.forename: Xingyu
authors.initials: X
authors.lastname: Wang
authors.forename: Alejandro
authors.initials: A
authors.lastname: Villagra
authors.forename: David
authors.initials: D
authors.lastname: Boulware
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Shain
authors.forename: Lori A
authors.initials: LA
authors.lastname: Hazlehurst
authors.forename: Melissa
authors.initials: M
authors.lastname: Alsina
authors.forename: Dung-Tsa
authors.initials: DT
authors.lastname: Chen
authors.forename: Amer A
authors.initials: AA
authors.lastname: Beg
authors.forename: William S
authors.initials: WS
authors.lastname: Dalton
mesh_terms: D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005199:Fanconi Anemia / Q000235:genetics / Q000378:metabolism*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008558:Melphalan / Q000494:pharmacology; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B; D011719:Pyrazines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051841:Transcription Factor RelB / Q000378:metabolism
chemical_list: C471109:4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; D001897:Boronic Acids; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D007093:Imidazoles; D016328:NF-kappa B; D011719:Pyrazines; D011810:Quinoxalines; C497593:RELB protein, human; D051841:Transcription Factor RelB; D000069286:Bortezomib; D008558:Melphalan