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J Biol Chem. 2015 May 15;290(20):12558-71. doi: 10.1074/jbc.M114.626960. Epub 2015 Mar 23.

Induction of heme oxygenase-1 by Na+-H+ exchanger 1 protein plays a crucial role in imatinib-resistant chronic myeloid leukemia cells.

Author information

1
From the Department of Hematology, Affiliated Hospital of Guiyang Medical University, Guiyang 550004, China, Department of Pharmacy, Affiliated BaiYun Hospital of Guiyang Medical University, Guiyang 550014, China.
2
Department of Pharmacy, Affiliated BaiYun Hospital of Guiyang Medical University, Guiyang 550014, China, Department of Pharmacy, Affiliated Hospital of Guiyang Medical University, Guiyang 550004, China, and.
3
From the Department of Hematology, Affiliated Hospital of Guiyang Medical University, Guiyang 550004, China, Guizhou Province Hematopoietic Stem Cell Transplantation Center and Key Laboratory of Hematological Disease Diagnostic and Treatment Centre, Guiyang 550004, China.
4
School of Pharmacy, Guiyang Medical University, Guiyang 550004, China.
5
From the Department of Hematology, Affiliated Hospital of Guiyang Medical University, Guiyang 550004, China, Guizhou Province Hematopoietic Stem Cell Transplantation Center and Key Laboratory of Hematological Disease Diagnostic and Treatment Centre, Guiyang 550004, China, wangjishi9646@163.com.

Abstract

Resistance toward imatinib (IM) and other BCR/ABL tyrosine kinase inhibitors remains troublesome in the treatment of advanced stage chronic myeloid leukemia (CML). The aim of this study was to estimate the reversal effects of down-regulation of Na(+)/H(+) exchanger 1 (NHE1) on the chemoresistance of BCR-ABL-positive leukemia patients' cells and cell lines. After treatment with the specific NHE1 inhibitor cariporide to decrease intracellular pH (pHi), the heme oxygenase-1 (HO-1) levels of the K562R cell line and cells from IM-insensitive CML patients decreased. HO-1, as a Bcr/Abl-dependent survival molecule in CML cells, is important for the resistance to tyrosine kinase inhibitors in patients with newly diagnosed CML or IM-resistant CML. Silencing PKC-β and Nrf-2 or treatment with inhibitors of p38 pathways obviously blocked NHE1-induced HO-1 expression. Furthermore, treatment with HO-1 or p38 inhibitor plus IM increased the apoptosis of the K562R cell line and IM-insensitive CML patients' cells. Inhibiting HO-1 enhanced the activation of caspase-3 and poly(ADP-ribose) polymerase-1. Hence, the results support the anti-apoptotic role of HO-1 induced by NHE1 in the K562R cell line and IM-insensitive CML patients and provide a mechanism by which inducing HO-1 expression via the PKC-β/p38-MAPK pathway may promote tumor resistance to oxidative stress.

KEYWORDS:

Na+/H+ ion exchanger 1; chronic myelogenous leukemia (CML); drug resistance; heme oxygenase; imatinib resistance; p38 MAPK; p38/mitogen-activated protein kinase; protein kinase C (PKC)

PMID:
25802333
PMCID:
PMC4432277
DOI:
10.1074/jbc.M114.626960
[Indexed for MEDLINE]
Free PMC Article

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