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Induction of apoptosis and differentiation by Na/H exchanger 1 modulation in acute myeloid leukemia cells

Authors
 Shin Young Hyun  ;  Eun Jung Na  ;  Ji Eun Jang  ;  Haerim Chung  ;  Soo Jeong Kim  ;  Jin Seok Kim  ;  Jee Hyun Kong  ;  Kwang Yong Shim  ;  Jong In Lee  ;  Yoo Hong Min  ;  June-Won Cheong 
Citation
 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, Vol.519(4) : 887-893, 2019 
Journal Title
 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 
ISSN
 0006-291X 
Issue Date
2019
Keywords
Acute myeloid leukemia ; Cytarabine ; HMA ; Leukemia cells ; Na/H exchanger 1 ; PMA
Abstract
We investigated the effect of the modulation of Na/H exchanger 1 (NHE1) on apoptosis, differentiation, and chemoresistance in acute myeloid leukemia (AML) cells to evaluate the possibility of NHE1 modulation as a novel therapeutic strategy for AML. The pHi of leukemia cell lines except KG1a was higher than that of normal bone marrow mononuclear cells (BM MNCs). Notably, in K562, cytarabine (AraC)-resistant OCI-AML2, and primary leukemia cells, pHi was significantly higher than that of normal BM MNCs. Western blotting and real-time quantitative PCR confirmed that the increased NHE1 expression was responsible for the higher pHi. Specifically, compared to CD34+CD38+ leukemia cells, the mean fluorescence intensity of NHE1 was significantly higher in CD34+CD38- leukemic stem cells. The out of range in pHi by treatment with an NHE inhibitor, the amiloride analogue 5-(N,N-hexamethylene) amiloride (HMA), or an NHE activator, phorbol 12-myristate 13-acetate (PMA), resulted in dose- and time-dependent inhibition of leukemia cell proliferation. PMA induced CD14+ differentiation of leukemia cells, whereas HMA induced cell cycle arrest at the G1 phase. HMA could induce apoptosis of leukemia cells even in AraC-resistant cells and showed an additive effect on apoptosis in AraC-sensitive cells. Our result revealed that AML cells prefer more alkalic intracellular moiety than normal BM MNCs following increased NHE1 expression and that NHE1 modulation can induce apoptosis and differentiation of AML cells. These findings imply that NHE1 is a potential target in cytotoxic or differentiation-induction treatment for AML.
Full Text
https://www.sciencedirect.com/science/article/pii/S0006291X19318170
DOI
10.1016/j.bbrc.2019.09.087
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Soo Jeong(김수정) ORCID logo https://orcid.org/0000-0001-8859-3573
Kim, Jin Seok(김진석) ORCID logo https://orcid.org/0000-0001-8986-8436
Min, Yoo Hong(민유홍) ORCID logo https://orcid.org/0000-0001-8542-9583
Jang, Ji Eun(장지은) ORCID logo https://orcid.org/0000-0001-8832-1412
Cheong, June-Won(정준원) ORCID logo https://orcid.org/0000-0002-1744-0921
Chung, Hae Rim(정해림) ORCID logo https://orcid.org/0000-0002-7926-9285
Hyun, Shin Yong(현신영)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/173286
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