title: The expression of P-glycoprotein in leukemia cells is associated with the upregulated expression of nestin, a class 6 filament protein.
abstract: Multidrug resistance (MDR) is a serious obstacle to the effective chemotherapeutic treatment of leukemia. Expression of plasma membrane P-glycoprotein (P-gp), a transporter involved in drug efflux, is the most frequently observed molecular causality of MDR. We observed the coexpression of P-gp and the filament protein nestin in the acute myeloid leukemia (AML) cell lines SKM-1 and MOLM-13 following the induction of P-gp expression using vincristine. Nestin is considered a marker of neural stem cells and neural progenitor cells. The aim of this study was to determine whether there is causal relationship between the expression of P-glycoprotein and the expression of nestin in both of these AML cell lines. The expression of P-gp was induced in SKM-1 cells by selective pressure using vincristine (VCR), mitoxantrone (MTX), azacytidine (AzaC) and lenalidomide (LEN). Whereas the selective pressure of VCR, MTX and AzaC also induced P-gp expression in MOLM-13 cells, LEN was found to be ineffective in this regard. In all cases in which P-gp expression was induced in SKM-1 and MOLM-13 cells, its expression was associated with the induction of nestin mRNA expression and the presence of a 200-220kDa nestin-immunoreactive protein band in western blots. Silencing P-gp expression using s10418 siRNA (known as the P-gp silencer) was associated with the downregulation of the nestin transcript level, demonstrated using RT-PCR. Nestin mRNA was also observed in two P-gp-positive variants of L1210 cells that were obtained either by selection with VCR or by transfection with a retrovirus encoding human P-gp. Detectable levels of nestin transcripts were not observed in P-gp-negative parental L1210 cells. Taken together, these results indicated that the induction of P-gp expression is causally associated with the expression of nestin in leukemia cells.
authors.affiliation: Institute of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology, Radlinskeho 9, 812 37 Bratislava, Slovak Republic.
authors.forename: Martina
authors.initials: M
authors.lastname: Coculova
authors.affiliation: Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Dúbravska cesta 9, 840 05 Bratislava, Slovak Republic.
authors.forename: Denisa
authors.initials: D
authors.lastname: Imrichova
authors.affiliation: Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Dúbravska cesta 9, 840 05 Bratislava, Slovak Republic.
authors.forename: M
authors.initials: M
authors.lastname: Seres
authors.affiliation: Institute of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology, Radlinskeho 9, 812 37 Bratislava, Slovak Republic; Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Dúbravska cesta 9, 840 05 Bratislava, Slovak Republic.
authors.forename: Lucia
authors.initials: L
authors.lastname: Messingerova
authors.affiliation: Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Dúbravska cesta 9, 840 05 Bratislava, Slovak Republic.
authors.forename: Viera
authors.initials: V
authors.lastname: Bohacova
authors.affiliation: Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Dúbravska cesta 9, 840 05 Bratislava, Slovak Republic. Electronic address: zdena.sulova@savba.sk.
authors.forename: Zdena
authors.initials: Z
authors.lastname: Sulova
authors.affiliation: Institute of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology, Radlinskeho 9, 812 37 Bratislava, Slovak Republic; Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Dúbravska cesta 9, 840 05 Bratislava, Slovak Republic. Electronic address: albert.breier@stuba.sk.
authors.forename: Albert
authors.initials: A
authors.lastname: Breier
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D064231:Nestin / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation; D014750:Vincristine / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D064231:Nestin; D012333:RNA, Messenger; D014750:Vincristine
keywords: L1210 cells; MOLM-13 cells; Multidrug resistance; Nestin; P-glycoprotein; SKM-1 cells