title: Induction of heme oxygenase-1 by Na+-H+ exchanger 1 protein plays a crucial role in imatinib-resistant chronic myeloid leukemia cells.
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.
authors: 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.
authors: Dan
authors: D
authors: Ma
authors: 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.
authors: Qin
authors: Q
authors: Fang
authors: 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.
authors: Ping
authors: P
authors: Wang
authors: 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.
authors: Rui
authors: R
authors: Gao
authors: 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.
authors: Weibing
authors: W
authors: Wu
authors: School of Pharmacy, Guiyang Medical University, Guiyang 550004, China.
authors: Tangsheng
authors: T
authors: Lu
authors: School of Pharmacy, Guiyang Medical University, Guiyang 550004, China.
authors: Lu
authors: L
authors: Cao
authors: 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.
authors: Xiuying
authors: X
authors: Hu
authors: 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.
authors: Jishi
authors: J
authors: Wang
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001549:Benzamides / Q000494:pharmacology*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects / Q000235:genetics; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008297:Male; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology*; D064546:Protein Kinase C beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism*
chemical_list: D001549:Benzamides; D027682:Cation Transport Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009363:Neoplasm Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D000068877:Imatinib Mesylate; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C579054:PRKCB protein, human; D064546:Protein Kinase C beta
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)