Abstract
BackgroundAberrant activation of β-catenin has been shown to play important roles in the chemoresistance of acute lymphoblastic leukemia (ALL), but the involvement and mechanism of β-catenin in methotrexate (MTX) resistance is poorly understood. In the present study, we demonstrate a critical role of β-catenin-NF-κB-FPGS pathway in MTX resistance in the human T-lineage ALL cell lines.MethodsLentivirus sh-β-catenin was used to silence the expression of β-catenin. Flow cytometry was performed to detect apoptosis after MTX treatment. Western blot, real-time PCR, Co-immunoprecipitation (Co-IP), Chromatin immunoprecipitation (ChIP), Re-ChIP, and Luciferase assay were utilized to investigate the relationship among β-catenin, nuclear factor (NF)-κB, and folypoly-γ-glutamate synthetase (FPGS).ResultsDepletion of β-catenin significantly increased the cytotoxicity of MTX. At the molecular level, knockdown of β-catenin caused the increase of the protein level of FPGS and NF-κB p65. Furthermore, β-catenin complexed with NF-κB p65 and directly bound to the FPGS promoter to regulate its expression. In addition, β-catenin repression prolonged the protein turnover of FPGS.ConclusionsTaken together, our results demonstrate that β-catenin may contribute to MTX resistance in leukemia cells via the β-catenin-NF-κB-FPGS pathway, posing β-catenin as a potential target for combination treatments during ALL therapy.
Highlights
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that accounts for about 15% of pediatric acute lymphoblastic leukemia
Taken together, our results demonstrate that β-catenin may contribute to MTX resistance in leukemia cells via the β-catenin-nuclear factor (NF)-κB-Folypolyγ-glutamate synthetase (FPGS) pathway, posing β-catenin as a potential target for combination treatments during ALL therapy
Reduction of β‐catenin expression decreases MTX resistance in T‐ALL cells To investigate the effect of β-catenin on MTX resistance, Jurkat and MOLT4 cells expressing high levels of β-catenin (Additional file 2: Figure S1) were transfected with β-catenin RNAi lentivirus for 48 h and treated with 10 μM MTX for an additional 24 h
Summary
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that accounts for about 15% of pediatric acute lymphoblastic leukemia. Understanding the Methotrexate (MTX) is a major component in all contemporary treatment protocols for childhood ALL, but emergence of resistance to MTX remains an obstacle towards curative chemotherapy [3, 4]. The ability of leukemia cells to accumulated MTXPGs was shown to be a determinant of MTX activity in childhood ALL patients. Loss of FPGS activity is a well-established mechanism of resistance to MTX in vitro and in vivo [5,6,7]. Aberrant activation of β-catenin has been shown to play important roles in the chemoresistance of acute lymphoblastic leukemia (ALL), but the involvement and mechanism of β-catenin in methotrexate (MTX) resist‐ ance is poorly understood. We demonstrate a critical role of β-catenin-NF-κB-FPGS pathway in MTX resistance in the human T-lineage ALL cell lines
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