Knocking down low molecular weight protein tyrosine phosphatase (LMW-PTP) reverts chemoresistance through inactivation of Src and Bcr-Abl proteins

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...

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Bibliographic Details
Published in:PloS one 2012-09, Vol.7 (9), p.e44312-e44312
Main Authors: Ferreira, Paula A, Ruela-de-Sousa, Roberta R, Queiroz, Karla C S, Souza, Ana Carolina S, Milani, Renato, Pilli, Ronaldo Aloise, Peppelenbosch, Maikel P, den Hertog, Jeroen, Ferreira, Carmen V
Format: Article
Language:English
Subjects:
Abl protein
Antineoplastic Agents - pharmacology
ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism
BCR protein
Bioassays
Biochemistry
Biological assays
Biology
Cancer therapies
Caspase 3 - metabolism
Cell cycle
Cell Line, Tumor
Cell Survival
Chemoresistance
Chemotherapy
Chronic myeloid leukemia
Deactivation
Drug Resistance, Neoplasm
Fusion protein
Fusion Proteins, bcr-abl - genetics
Fusion Proteins, bcr-abl - metabolism
Fusion Proteins, bcr-abl - physiology
Gastroenterology
Gene Expression Regulation, Leukemic
Hepatology
Humans
Imatinib
Imatinib mesylate
Immunoglobulins
Inactivation
K562 Cells
Kinases
Laboratories
Leukemia
Low molecular weights
Medical prognosis
Medical research
Medicine
Microbial drug resistance
Molecular Weight
Multidrug resistance
Myeloid leukemia
Pancreatic cancer
Phenols (Class of compounds)
Phenotypes
Phosphatase
Phosphatases
Phosphorylation
Protein Tyrosine Phosphatases - antagonists & inhibitors
Protein Tyrosine Phosphatases - genetics
Protein-tyrosine-phosphatase
Proteins
Signal transduction
Src protein
src-Family Kinases - metabolism
Tyrosine
Vincristine
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0044312