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

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

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).

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Benzamides / pharmacology*
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism*
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • Enzyme Induction / drug effects
  • Enzyme Induction / genetics
  • Female
  • Gene Expression Regulation, Leukemic
  • Heme Oxygenase-1 / biosynthesis*
  • Heme Oxygenase-1 / genetics
  • Humans
  • Imatinib Mesylate
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / genetics
  • Male
  • Middle Aged
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Oxidative Stress / drug effects
  • Oxidative Stress / genetics
  • Piperazines / pharmacology*
  • Protein Kinase C beta / antagonists & inhibitors
  • Protein Kinase C beta / genetics
  • Protein Kinase C beta / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / pharmacology*
  • Sodium-Hydrogen Exchanger 1
  • Sodium-Hydrogen Exchangers / genetics
  • Sodium-Hydrogen Exchangers / metabolism*

Substances

  • Benzamides
  • Cation Transport Proteins
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Neoplasm Proteins
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • SLC9A1 protein, human
  • Sodium-Hydrogen Exchanger 1
  • Sodium-Hydrogen Exchangers
  • Imatinib Mesylate
  • HMOX1 protein, human
  • Heme Oxygenase-1
  • PRKCB protein, human
  • Protein Kinase C beta