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

March 23rd, 2015 by Ma, D., Fang, Q., Wang, P., Gao, R., Wu, W., Lu, T., Cao, L., Hu, X., Wang, J.

Resistance toward imatinib (IM) and other BCR/ABL tyrosine kinase inhibitors (TKIs) 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 specific NHE1 inhibitor cariporide to decrease intracellular pH (pHi), the heme oxygenase-1 (HO-1) levels of 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 to resist TKIs in patients with newly diagnosed CML or IM-resistant CML. Silencing protein kinase C-β (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 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 K562R cell line and IM-insensitive CML patients, and provide a mechanism by which inducing HO-1 expression via the PKC-β/p38-MAPK (mitogen-activated protein kinase) pathway may promote tumor resistance to oxidative stress.
  • Posted in Journal of Biological Chemistry, Publications
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