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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 |
ISSN | 0390-6078 |
卷号 | 104期号:1页码:102-112 |
发表状态 | 已发表 |
DOI | 10.3324/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 |
推荐引用方式 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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