title: Knocking down low molecular weight protein tyrosine phosphatase (LMW-PTP) reverts chemoresistance through inactivation of Src and Bcr-Abl proteins.
abstract: The development of multidrug resistance (MDR) limits the efficacy of continuous chemotherapeutic treatment in chronic myelogenous leukemia (CML). Low molecular weight protein tyrosine phosphatase (LMW-PTP) is up-regulated in several cancers and has been associated to poor prognosis. This prompted us to investigate the involvement of LMW-PTP in MDR. In this study, we investigated the role of LMW-PTP in a chemoresistant CML cell line, Lucena-1. Our results showed that LMW-PTP is highly expressed and 7-fold more active in Lucena-1 cells compared to K562 cells, the non-resistant cell line. Knocking down LMW-PTP in Lucena-1 cells reverted chemoresistance to vincristine and imatinib mesylate, followed by a decrease of Src and Bcr-Abl phosphorylation at the activating sites, inactivating both kinases. On the other hand, overexpression of LMW-PTP in K562 cells led to chemoresistance to vincristine. Our findings describe, for the first time, that LMW-PTP cooperates with MDR phenotype, at least in part, through maintaining Src and Bcr-Abl kinases in more active statuses. These findings suggest that inhibition of LMW-PTP may be a useful strategy for the development of therapies for multidrug resistant CML.
authors.affiliation: Laboratory of Bioassays and Signal Transduction, Biochemistry Department, Biology Institute, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
authors.forename: Paula A
authors.initials: PA
authors.lastname: Ferreira
authors.forename: Roberta R
authors.initials: RR
authors.lastname: Ruela-de-Sousa
authors.forename: Karla C S
authors.initials: KC
authors.lastname: Queiroz
authors.forename: Ana Carolina S
authors.initials: AC
authors.lastname: Souza
authors.forename: Renato
authors.initials: R
authors.lastname: Milani
authors.forename: Ronaldo Aloise
authors.initials: RA
authors.lastname: Pilli
authors.forename: Maikel P
authors.initials: MP
authors.lastname: Peppelenbosch
authors.forename: Jeroen
authors.initials: J
authors.lastname: den Hertog
authors.forename: Carmen V
authors.initials: CV
authors.lastname: Ferreira
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D020014:K562 Cells; D008970:Molecular Weight; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D016044:Fusion Proteins, bcr-abl; D019061:src-Family Kinases; D017027:Protein Tyrosine Phosphatases; D053148:Caspase 3