?-catenin promotes MTX resistance of leukemia cells by down-regulating FPGS expression via NF-?B.

ABSTRACT:

Background

Aberrant activation of ?-catenin has been shown to play important roles in the chemoresistance of acute lymphoblastic leukemia (ALL), but the involvement and mechanism of ?-catenin in methotrexate (MTX) resistance is poorly understood. In the present study, we demonstrate a critical role of ?-catenin-NF-?B-FPGS pathway in MTX resistance in the human T-lineage ALL cell lines.

Methods

Lentivirus sh-?-catenin was used to silence the expression of ?-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 ?-catenin, nuclear factor (NF)-?B, and folypoly-?-glutamate synthetase (FPGS).

Results

Depletion of ?-catenin significantly increased the cytotoxicity of MTX. At the molecular level, knockdown of ?-catenin caused the increase of the protein level of FPGS and NF-?B p65. Furthermore, ?-catenin complexed with NF-?B p65 and directly bound to the FPGS promoter to regulate its expression. In addition, ?-catenin repression prolonged the protein turnover of FPGS.

Conclusions

Taken together, our results demonstrate that ?-catenin may contribute to MTX resistance in leukemia cells via the ?-catenin-NF-?B-FPGS pathway, posing ?-catenin as a potential target for combination treatments during ALL therapy.

SUBMITTER: Liu SG 

PROVIDER: S-EPMC7313175 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature