Pharmacologically targeting molecular motor promotes mitochondrial fission for anti-cancer

作     者：Yi Qian Meimei Zhao Qinghua Han Jingkang Wang Lixi Liao Heng Yang Dan Liu Pengfei Tu Hong Liang Kewu Zeng Yi Qian;Meimei Zhao;Qinghua Han;Jingkang Wang;Lixi Liao;Heng Yang;Dan Liu;Pengfei Tu;Hong Liang;Kewu Zeng

作者机构：State Key Laboratory of Natural and Biomimetic DrugsSchool of Pharmaceutical SciencesPeking UniversityBeijing 100191China Proteomics LaboratoryMedical and Healthy Analytical CenterPeking University Health Science CenterBeijing 100191China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2021年第11卷第7期

页      面：1853-1866页

核心收录：

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

基　　金：supported by the National Key Technology R&D Program“New Drug Innovation”of China[Nos.2019YFC1711000 and 2019YFC1708902] the National Natural Science Foundation of China[Nos.81973505 and 81773932] 

主　　题：Anti-cancer Liver hepatocellular carcinoma Mitochondrial fission Small molecule Target identification Molecular motor MYH9 HSPA9 

摘      要：Mitochondrial shape rapidly changes by dynamic balance of fusion and fission to adjust to constantly changing energy demands of cancer *** dynamics balance is exactly regulated by molecular motor consisted of myosin and actin cytoskeleton ***,targeting myosin eactin molecular motor is considered as a promising strategy for *** this study,we performed a proof-of-concept study with a natural-derived small-molecule J13 to test the feasibility of anti-cancer therapeutics via pharmacologically targeting molecular ***,we found J13 could directly target myosin-9(MYH9)eactin molecular motor to promote mitochondrial fission progression,and markedly inhibited cancer cells survival,proliferation and *** study revealed that J13 impaired MYH9 eactin interaction to inactivate molecular motor,and caused a cytoskeleton-dependent mitochondrial dynamics ***,stable isotope labeling with amino acids in cell culture(SILAC)technology-coupled with pulldown analysis identified HSPA9 as a crucial adaptor protein connecting MYH9 eactin molecular motor to mitochondrial *** together,we reported the first natural small-molecule directly targeting MYH9 eactin molecular motor for anti-cancer translational ***,our study also proved the conceptual practicability of pharmacologically disrupting mitochondrial fission/fusion dynamics in human cancer therapy.