Amiodarone induces autophagy/mitophagy by activating sirtuin-3 in acute myelocytic leukemia

作     者：ZHANG Jin SUN De-juan ZHANG Lan OU Yang-liang 

作者机构：State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital Sichuan University School of Life Science and EngineeringSouthwest Jiaotong University 

出 版 物：《中国药理学与毒理学杂志》 (Chinese Journal of Pharmacology and Toxicology)

年 卷 期：2019年第10期

页      面：778-779页

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：National Natural Science Foundation of China(81602627 and 81803365) 

主　　题：amiodarone sirtuin-3 activator autophagy mitophagy acute myelocytic leukemia 

摘      要：OBJECTIVE To find a new treatment strategy foracute myelocytic leukemia(AML), we tried to find new targets. Sirtuin-3(SIRT3), a NAD+-dependent protein deacetylase localized primarily in the mitochondrion,is well-known to regulate autophagy, which is an evolutionarily conserved, multi-step lysosomal degradation process and also implicated in many diseases, such as *** evidence has revealed that SIRT3 may act as a tumor suppressor in AML, and thus activating SIRT3 will represent a potential therapeutic *** Aotophagy related protein expression and SIRT3 were analyzed by The Cancer Genome Atlas(TCGA)analysis. SIRT3 activator was selected by using in silico screening and anti-proliferative activities. The target selectivity of amiodarone was determined by co-crystal structure and deacetylase activity assays. The mechanisms of amiodarone-induced autophagy/mitophagy were investigated by fluorescence microscope, Western blotting, flow cytometry analysis, immunocytochemistry, as well as i TRAQ-based proteomics analysis. The therapeutic effect of amiodarone was assessed by xenograft AML mouse model. RESULTS TCGA dataset, we identified that SIRT3 was a key prognostic factor in AML, which was closely associated with the survival of patients. Subsequently, we computationally and experimentally screened a series of candidate activators of SIRT3 from Drugbank,and found the best candidate compound amiodarone,which was further validated by co-crystal structure of SIRT3/amiodarone. Interestingly, amiodarone induced autophagy via SIRT3-mediated AMPK-m TOR-ULK1-Beclin-1 pathway in U937 and HL-60 cells. Moreover,this activator induced mitophagy via SIRT3-deacetylating FOXO3 a and thus triggering PINK1/Parkin pathway in AML cells. The i TRAQ-based proteomics analyses revealed that amiodarone induced mitophagy by downregulating 14-3-3γ, upregulating and deacetylating Beclin-1,as well as activating FOXO3 a-HIF1α-BNIP3 and *** is more, deacetylation proteomics