2-Bromopalmitate targets retinoic acid receptor alpha and overcomes all-trans retinoic acid resistance of acute promyelocytic leukemia
Lu, Ying1; Yan, Jin-Song2; Xia, Li1; Qin, Kang1; Yin, Qian-Qian3; Xu, Hong-Tao3; Gao, Meng-Qing2; Qu, Xiao-Ning2; Sun, Yu-Ting2; Chen, Guo-Qiang1
2019-01
发表期刊HAEMATOLOGICA
ISSN0390-6078
卷号104期号:1页码:102-112
发表状态已发表
DOI10.3324/haematol.2018.191916
摘要Fatty acid oxidation dependency of leukemia cells has been documented in recent studies. Pharmacologic inhibition of fatty acid oxidation, thereby, displays significant effects in suppressing leukemia. 2-Bromopalmitate, a palmitate analogue, was initially identified as an inhibitor of fatty acid oxidation, and recently recognized as an inhibitor of protein palmitoylation. However, the effects of 2-Bromopalmitate on leukemia and its cellular targets remain obscure. Herein, we discover in cultured cell lines, a transplantable mouse model, and primary blasts that 2-Bromopalmitate presents synergistic differentiation induction with all-trans retinoic acid in acute promyelocytic leukemia. Moreover, 2-Bromopalmitate overcomes all-trans retinoic acid resistance in all-trans retinoic acid-resistant cells and leukemic mice. Mechanistically, 2-Bromopalmitate covalently binds at cysteine 105 and cysteine 174 of retinoic acid receptor alpha (RAR alpha) and stabilizes RARa protein in the presence of all-trans retinoic acid which is known to induce RARa degradation, leading to enhanced transcription of RAR alpha-target genes. Mutation of both cysteines largely abrogates the synergistic effect of 2-Bromopa lmitate on all-trans retinoic acid-induced differentiation, demonstrating that 2-Bromopalmitate promotes all-trans retinoic acid-induced differentiation through binding RARa. All-trans retinoic acid-based regimens including arsenic trioxide or chemotherapy, as preferred therapy for acute promyelocytic leukemia, induce adverse events and irreversible resistance. We expect that combining all-trans retinoic acid with 2-Bromopalmitate would be a promising therapeutic strategy for acute promyelocytic leukemia, especially for overcoming all-trans retinoic acid resistance of relapsed acute promyelocytic leukemia patients.
收录类别SCI ; SCIE
语种英语
资助项目Reformation Project in the Key Clinical Departments of Provincial Hospitals on Construction of Diagnosis and Treatment Capacity in Liaoning Province[LNCCC-A02-2015]
WOS研究方向Hematology
WOS类目Hematology
WOS记录号WOS:000457454500026
出版者FERRATA STORTI FOUNDATION
WOS关键词PML-RAR-ALPHA ; ARSENIC TRIOXIDE AS2O3 ; PROTEIN PALMITOYLATION ; CELL-DIFFERENTIATION ; PML/RAR-ALPHA ; OXIDATION ; DEGRADATION ; INHIBITION ; CANCER ; ONCOPROTEIN
原始文献类型Article
引用统计
文献类型期刊论文
条目标识符https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/30220
专题免疫化学研究所_特聘教授组_抗体化学实验室
免疫化学研究所_特聘教授组_抗体设计学实验室
通讯作者Chen, Guo-Qiang
作者单位1.Shanghai Jiao Tong Univ, Chinese Minist Educ, Dept Pathophysiol, Key Lab Cell Differentiat & Apoptosis,Sch Med, Shanghai, Peoples R China
2.Dalian Med Univ, Dept Hematol, Liaoning Med Ctr Hematopoiet Stem Cell Transplant, Dalian Key Lab Hematol,Hosp 2, Dalian, Peoples R China
3.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai, Peoples R China
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GB/T 7714
Lu, Ying,Yan, Jin-Song,Xia, Li,et al. 2-Bromopalmitate targets retinoic acid receptor alpha and overcomes all-trans retinoic acid resistance of acute promyelocytic leukemia[J]. HAEMATOLOGICA,2019,104(1):102-112.
APA Lu, Ying.,Yan, Jin-Song.,Xia, Li.,Qin, Kang.,Yin, Qian-Qian.,...&Chen, Guo-Qiang.(2019).2-Bromopalmitate targets retinoic acid receptor alpha and overcomes all-trans retinoic acid resistance of acute promyelocytic leukemia.HAEMATOLOGICA,104(1),102-112.
MLA Lu, Ying,et al."2-Bromopalmitate targets retinoic acid receptor alpha and overcomes all-trans retinoic acid resistance of acute promyelocytic leukemia".HAEMATOLOGICA 104.1(2019):102-112.
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