Autophagy is an important event for low-dose cytarabine treatment in acute myeloid leukemia cells. (September 2017)

• Record Type: Journal Article
• Authors: Chen, Liyun; Guo, Pei; Zhang, Yunxiang; Li, Xiaoyang; Jia, Peimin; Tong, Jianhua; Li, Junmin
• Is Part Of: Leukemia research. Volume 60(2017:Sep.)
• Page Start: 44
• Page End: 52
• Publication Date: 2017-09
• Subjects: AML acute myeloid leukemia -- Ara-c arabinoside cytarabine -- LD Ara-C low-dose Ara-c -- G-CSF granulocyte colony-stimulating factor -- DNA deoxyribonucleic acid -- BH-3 Bcl-2-homology-3 -- PI propidium iodide -- LC3 microtubule associated protein 1 light chain 3 alpha -- CQ chloroquine -- SQSTM1/p62 sequestosome 1 -- TEM transmission electron microscope -- mTOR mammalian target of rapamycin -- PI3K phosphoinositide 3-kinases -- p70S6K ribosomal protein S6 kinase B1 -- 4EBP1 eukaryotic translation initiation factor 4E-binding protein 1 -- AMPK AMP-activated protein kinase -- ERK extracellular signal-regulated kinases -- 3-MA 3-methyladenine -- shRNA short hairpin ribonucleic acid -- HD Ara-c high-dose Ara-c -- ATG5 autophagy-related 5 -- ATG7 autophagy-related 7 -- Raf-1 Ras-proto-oncogene serine/threonine-protein kinase -- MEK mitogen-activated protein kinase -- LKB1 liver kinase B1 -- FLT3 FMS-like receptor tyrosine kinase-3 -- HRP horseradish peroxidase; Cytarabine -- Acute myeloid leukemia -- Autophagy -- Differentiation -- Beclin1 -- Akt-mTOR pathway; Leukemia -- Periodicals; Leukemia -- Periodicals; Leucémie -- Périodiques; Leukemia; Periodicals; Electronic journals; Electronic journals; 616.9941905
• DOI: 10.1016/j.leukres.2017.06.007
• Languages: English
• ISSNs: 0145-2126

Abstract

Highlights: Low-dose Ara-C does not cause apoptosis but induces differentiation of leukemic cells. Low dose Ara-C can induce autophagy in U937 and HEL cells. Autophagy is essential in differentiation and death of AML cells in vitro . Beclin-1 upregulation is indispensable for AML cell differentiation. mTOR pathway is required for low-dose Ara-C-induced autophagy. Abstract: Cytarabine (Ara-c) has been an important agent in acute myeloid leukemia (AML) treatment for more than 40 years. While, the mechanisms underlying low dose cytarabine (LD Ara-c) is poorly understood. In this study, we investigated the therapeutic effect of LD Ara-C in vitro . U937 and HEL cell lines were treated with increasing dose of Ara-C and showed growth inhibition rates in a time and dose-dependent manner. Treatment with LD Ara-C (50 nM) induced a time-dependent increase in expression of microtubule-associated protein light chain 3 (LC3) and beclin1, but degradation of sequestosome1 (p62) in both U937 and HEL cells. Characteristic of autophagosomes appeared after 24 h treatment. Meanwhile, deregulation of Akt-mTOR pathway was also detected. When cultured in presence of autophagy inhibitors, autophagy and differentiation was reversed, and cell growth inhibition was also attenuated. Similar phenomenon could also be seen when beclin1 expression was down-regulated. Taken together, we concluded that LD Ara-C can induce autophagy in AML cells and appeared to play an important role in differentiation and death. Down-regulation of Akt-mTOR pathway is involved in these processes. We suggest that cytarabine-induced autophagy is not a pro-survival mechanism, but accounts for its antineoplastic effects.