title: MRP1 gene expression level regulates the death and differentiation response of neuroblastoma cells.
abstract: We have previously reported a strong correlation between poor prognosis in childhood neuroblastoma (NB) patients and high-level expression of the transmembrane efflux pump, Multidrug Resistance-associated Protein (MRP1), in NB tumour tissue. In this study, we inhibited the endogenous expression of MRP1 in 2 different NB tumour cell lines by stably transfecting an MRP1 antisense expression vector (MRP-AS). Compared with control cells, MRP-AS transfectant cells demonstrated a higher proportion of dead and morphologically apoptotic cells, spontaneous neuritogenesis, and, increased synaptophysin and neurofilament expression. Bcl-2 protein expression was markedly reduced in MRP-AS cells compared to controls. Conversely, we found that the same NB tumour cell line overexpressing the full-length MRP1 cDNA in sense orientation (MRP-S) demonstrated resistance to the neuritogenic effect of the differentiating agent, all-trans-retinoic acid. Taken together, the results suggest that the level of MRP1 expression in NB tumour cells may influence the capacity of NB cells for spontaneous regression in vivo through cell differentiation and death.
authors.affiliation: Children's Cancer Institute Australia for Medical Research, PO Box 81, Randwick, NSW 2031, Australia.
authors.forename: A E
authors.initials: AE
authors.lastname: Peaston
authors.forename: M
authors.initials: M
authors.lastname: Gardaneh
authors.forename: A V
authors.initials: AV
authors.lastname: Franco
authors.forename: J E
authors.initials: JE
authors.lastname: Hocker
authors.forename: K M
authors.initials: KM
authors.lastname: Murphy
authors.forename: M L
authors.initials: ML
authors.lastname: Farnsworth
authors.forename: D R
authors.initials: DR
authors.lastname: Catchpoole
authors.forename: M
authors.initials: M
authors.lastname: Haber
authors.forename: M D
authors.initials: MD
authors.lastname: Norris
authors.forename: R B
authors.initials: RB
authors.lastname: Lock
authors.forename: G M
authors.initials: GM
authors.lastname: Marshall
mesh_terms: D017209:Apoptosis; D002454:Cell Differentiation; D002455:Cell Division; D002999:Clone Cells; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D015870:Gene Expression; D006801:Humans; D020287:In Situ Nick-End Labeling; D008856:Microscopy, Fluorescence; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*; D016376:Oligonucleotides, Antisense / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014162:Transfection; D014212:Tretinoin / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D014212:Tretinoin; C421109:multidrug resistance-associated protein 1