title: Breast cancer resistance protein (BCRP/ABCG2) localises to the nucleus in glioblastoma multiforme cells.
abstract: The breast cancer resistance protein (BCRP), an ATP binding cassette (ABC) efflux transporter, plays a role in multiple drug resistance (MDR). Previous studies of the subcellular location of the ABC transporter P-glycoprotein indicated that this protein is expressed in nuclear membranes. This study examines the nuclear distribution of BCRP in seven human-derived glioblastoma (GBM) and astrocytoma cell lines. BCRP expression was observed in the nuclear extracts of 6/7 cell lines. Using the GBM LN229 cell line as a model, nuclear BCRP protein was detected by immunoblotting and confocal laser microscopy. Importantly, nuclear BCRP staining was found in a subpopulation of tumour cells in a human brain GBM biopsy. Mitoxantrone cytotoxicity in the LN229 cell line was determined with and without the BCRP inhibitor fumitremorgin C (FTC) and after downregulation of BCRP with small interfering RNA (siRNA). FTC inhibition of BCRP increased mitoxantrone cytotoxicity with a ~7-fold reduction in the IC₅₀ and this effect was further potentiated in the siRNA-treated cells. In conclusion, BCRP is expressed in the nuclear extracts of select GBM and astrocytoma cell lines and in a human GBM tumour biopsy. Its presence in the nucleus of cancer cells suggests new role for BCRP in MDR.
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging-NIA/NIH, Baltimore, MD, USA.
authors.forename: Prateek
authors.initials: P
authors.lastname: Bhatia
authors.forename: Michel
authors.initials: M
authors.lastname: Bernier
authors.forename: Mitesh
authors.initials: M
authors.lastname: Sanghvi
authors.forename: Ruin
authors.initials: R
authors.lastname: Moaddel
authors.forename: Roland
authors.initials: R
authors.lastname: Schwarting
authors.forename: Anuradha
authors.initials: A
authors.lastname: Ramamoorthy
authors.forename: Irving W
authors.initials: IW
authors.lastname: Wainer
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001254:Astrocytoma / Q000378:metabolism / Q000473:pathology; D001706:Biopsy; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D015151:Immunoblotting; D007211:Indoles / Q000032:analysis / Q000494:pharmacology; D018613:Microscopy, Confocal; D008942:Mitoxantrone / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D007211:Indoles; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D008942:Mitoxantrone; C010522:tryptoquivaline