title: Choline kinase overexpression increases invasiveness and drug resistance of human breast cancer cells.
abstract: A direct correlation exists between increased choline kinase (Chk) expression, and the resulting increase of phosphocholine levels, and histological tumor grade. To better understand the function of Chk and choline phospholipid metabolism in breast cancer we have stably overexpressed one of the two isoforms of Chk-alpha known to be upregulated in malignant cells, in non-invasive MCF-7 human breast cancer cells. Dynamic tracking of cell invasion and cell metabolism were studied with a magnetic resonance (MR) compatible cell perfusion assay. The MR based invasion assay demonstrated that MCF-7 cells overexpressing Chk-alpha (MCF-7-Chk) exhibited an increase of invasion relative to control MCF-7 cells (0.84 vs 0.3). Proton MR spectroscopy studies showed significantly higher phosphocholine and elevated triglyceride signals in Chk overexpressing clones compared to control cells. A test of drug resistance in MCF-7-Chk cells revealed that these cells had an increased resistance to 5-fluorouracil and higher expression of thymidylate synthase compared to control MCF-7 cells. To further characterize increased drug resistance in these cells, we performed rhodamine-123 efflux studies to evaluate drug efflux pumps. MCF-7-Chk cells effluxed twice as much rhodamine-123 compared to MCF-7 cells. Chk-alpha overexpression resulted in MCF-7 human breast cancer cells acquiring an increasingly aggressive phenotype, supporting the role of Chk-alpha in mediating invasion and drug resistance, and the use of phosphocholine as a biomarker of aggressive breast cancers.
authors.affiliation: JHU ICMIC Program, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Tariq
authors.initials: T
authors.lastname: Shah
authors.forename: Flonne
authors.initials: F
authors.lastname: Wildes
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Penet
authors.forename: Paul T
authors.initials: PT
authors.lastname: Winnard
authors.forename: Kristine
authors.initials: K
authors.lastname: Glunde
authors.forename: Dmitri
authors.initials: D
authors.lastname: Artemov
authors.forename: Ellen
authors.initials: E
authors.lastname: Ackerstaff
authors.forename: Barjor
authors.initials: B
authors.lastname: Gimi
authors.forename: Samata
authors.initials: S
authors.lastname: Kakkad
authors.forename: Venu
authors.initials: V
authors.lastname: Raman
authors.forename: Zaver M
authors.initials: ZM
authors.lastname: Bhujwalla
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002797:Choline Kinase / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D030781:Organisms, Genetically Modified; D010767:Phosphorylcholine / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D007527:Isoenzymes; D010767:Phosphorylcholine; D002797:Choline Kinase