Knocking Down Low Molecular Weight Protein Tyrosine Phosphatase (LMW-PTP) Reverts Chemoresistance through Inactivation of Src and Bcr-Abl Proteins

Paula A Ferreira,Renato Milani,Ronaldo Aloise Pilli,Jeroen Den Hertog,Karla C S Queiroz,Carmen V Ferreira,Ana Carolina S Souza,Roberta R Ruela-De-Sousa,Maikel P Peppelenbosch,Rafael Linden

doi:10.1371/journal.pone.0044312

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.

Highlights

Failure of cancer chemotherapy may occur due to increased efflux of chemotherapeutic agents, leading to reduction of intracellular drug levels and consequent drug insensitivity, often to multiple agents
It is clear that overexpression of Low molecular weight protein tyrosine phosphatase (LMW-PTP) protected the K562 cells against cell death induced by VCR. These results strongly suggest that LMW-PTP is involved in chemoresistance and its overexpression makes the cells more resistant
This study shows for the first time that LMW-PTP is involved in chemoresistance

Summary

Introduction

Failure of cancer chemotherapy may occur due to increased efflux of chemotherapeutic agents, leading to reduction of intracellular drug levels and consequent drug insensitivity, often to multiple agents. A well-established cause of multidrug resistance (MDR) involves increased expression of members of the ATPbinding cassette (ABC) transporter superfamily, which extrude various chemotherapeutic compounds from cells. In this context, resistance to chemotherapy is a major drawback in the effective treatment of chronic myelogenous leukemia (CML). Overexpression of LMW-PTP has been reported in several tumors and is generally associated with a proliferative phenotype and poor prognosis [5]. The LMW-PTP family has been reported to interact with several tyrosine kinases including PDGF [6], JAK2 [7], STAT5 [8], Insulin receptor, Eph Receptor [9] and EGF receptor [10]. The role of LMWPTP in CML has not yet been well characterized

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Conclusion