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Induction of cytosine arabinoside-resistant human myeloid leukemia cell death through autophagy regulation by hydroxychloroquine

Authors
 Yundeok Kim  ;  Ju-In Eom  ;  Hoi-Kyung Jeung  ;  Ji Eun Jang  ;  Jin Seok Kim  ;  June-Won Cheong  ;  Young Sam Kim  ;  Yoo Hong Min 
Citation
 Biomedicine & Pharmacotherapy, Vol.73 : 87-96, 2015 
Journal Title
 Biomedicine & Pharmacotherapy 
ISSN
 0753-3322 
Issue Date
2015
MeSH
Antimetabolites, Antineoplastic/pharmacology ; Antimetabolites, Antineoplastic/therapeutic use ; Autophagy/drug effects* ; Autophagy/physiology ; Cell Death/drug effects ; Cell Death/physiology ; Cytarabine/pharmacology ; Cytarabine/therapeutic use ; Drug Resistance, Neoplasm/drug effects* ; Drug Resistance, Neoplasm/physiology ; Humans ; Hydroxychloroquine/pharmacology* ; Hydroxychloroquine/therapeutic use ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/pathology* ; U937 Cells
Keywords
Acute myeloid leukemia ; Apoptosis ; Autophagy ; Chemoresistance ; Hydroxychloroquine
Abstract
We investigated the effects of the autophagy inhibitor hydroxychloroquine (HCQ) on cell death of cytosine arabinoside (Ara-C)-resistant human acute myeloid leukemia (AML) cells. Ara-C-sensitive (U937, AML-2) and Ara-C-resistant (U937/AR, AML-2/AR) human AML cell lines were used to evaluate HCQ-regulated cytotoxicity, autophagy, and apoptosis as well as effects on cell death-related signaling pathways. We found that HCQ-induced dose- and time-dependent cell death in Ara-C-resistant cells compared to Ara-C-sensitive cell lines. The extent of cell death and features of HCQ-induced autophagic markers including increase in microtubule-associated protein light chain 3 (LC3) I conversion to LC3-II, beclin-1, ATG5, as well as green fluorescent protein-LC3 positive puncta and autophagosome were remarkably greater in U937/AR cells. Also, p62/SQSTM1 was increased in response to HCQ. p62/SQSTM1 protein interacts with both LC3-II and ubiquitin protein and is degraded in autophagosomes. Therefore, a reduction of p62/SQSTM1 indicates increased autophagic degradation, whereas an increase of p62/SQSTM1 by HCQ indicates inhibited autophagic degradation. Knock down of p62/SQSTM1 using siRNA were prevented the HCQ-induced LC3-II protein level as well as significantly reduced the HCQ-induced cell death in U937/AR cells. Also, apoptotic cell death and caspase activation in U937/AR cells were increased by HCQ, provided evidence that HCQ-induced autophagy blockade. Taken together, our data show that HCQ-induced apoptotic cell death in Ara-C-resistant AML cells through autophagy regulation.
Full Text
http://www.sciencedirect.com/science/article/pii/S0753332215001250
DOI
10.1016/j.biopha.2015.05.012
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Young Sam(김영삼) ORCID logo https://orcid.org/0000-0001-9656-8482
Kim, Yun Deok(김윤덕) ORCID logo https://orcid.org/0000-0002-5336-7936
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
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/141263
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