NHE1 has a notable role in metastasis and drug resistance of T-cell acute lymphoblastic leukemia

Abstract

Abstract. T-cell acute lymphoblastic leukemia (T-ALL) represents a spectrum of hematological malignancies that affect human health. Metastasis and chemotherapeutic drug resistance are the primary causes of mortality in patients with T-ALL. Sodium-hydrogen antiporter 1 (NHE1) is established to serve a role in metastasis and drug resistance in numerous types of cancer; however, the function of NHE1 in T-ALL remains to be elucidated. Previously, the C-C-motif chemokine ligand 25 (CCL25) was identified to be involved in metastasis and drug resistance in the MOLT4 T-ALL cell line, as was the ezrin protein. The present study investigated the role of NHE1 in the metastasis of T-ALL using a Transwell assay and scanning electron microscopy, using MOLT4 cells as a model. The association between NHE1 and ezrin was assessed using laser scanning confocal microscopy. The effect of NHE1 on resistance to the chemotherapy drug doxorubicin (DOX) was also investigated using a cell viability and cytotoxicity assay. Expression of NHE1 increased following treatment with CCL25, accompanied by morphological changes in MOLT4 cells and the co-localization of NHE1 with ezrin. In addition, wild-type MOLT4 cells exhibited an increased polarization ability compared with NHE1-or ezrin-silenced cells. NHE1-or ezrin-silenced cells exhibited higher sensitivity to DOX compared with wild-type MOLT4 cells. In conclusion, the increased expression or activity of NHE1 may potentially be a poor prognostic indicator for human T-ALL.

Elevated Na/H exchanger 1 (SLC9A1) emerges as a marker for tumorigenesis and prognosis in gliomas

“…Taken together, our analysis (>1000 glioma cases) strongly suggests that NHE1 protein is involved in glioma tumorigenesis and progression. The underlying mechanisms could include promoting tumor proliferation and invasion [ 37 – 41 ]. Our gene ontology analysis indicates that NHE1 protein is involved in the tumor migration and invasion by the regulation of cell adhesion and extracellular matrix organization.…”

Perspectives for Targeting Ezrin in Cancer Development and Progression

“…In T-cell acute lymphoblastic leukemia cells, ERM phosphorylation has been found to promote invasion [51], and EZR deregulation has been related to the progression of mouse preleukemia erythroblasts toward malignancy [52]. In acute myeloid leukemia cells, functional studies have shown that EZR promotes survival and acts as an effector protein in cell signaling mediated by FLT3-ITD and mutated KIT receptors [52][53][54].…”

Plant-derived extracts and metabolic modulation in leukemia: a promising approach to overcome treatment resistance

“…in the microenvironment plays an immunosuppressive role and mediates the protonation of drugs, affecting their cell permeability (Altaf et al, 2017;de la Cruz-López et al, 2019). In T-ALL, increased NHE1 activity may promote resistance to DOX and imatinib (Man et al, 2014).…”