Identification of HMGCR as the anticancer target of physapubenolide against melanoma cells by in silico target prediction  

作　　者：Hai-yan Wang Pian Yu Xi-sha Chen Hui Wei Shi-jie Cao Meng Zhang Yi Zhang Yong-guang Tao Dong-sheng Cao Feng Qiu Yan Cheng 

机构地区：[1]Department of Pharmacy,The Second Xiangya Hospital,Central South University,Changsha 410011,China [2]Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug,Changsha 410011,China [3]Xiangya School of Pharmaceutical Sciences,Central South University,Changsha 410008,China [4]School of Chinese Materia Medica and Tianjin State Key Laboratory of Modern Chinese Medicine,Tianjin University of Traditional Chinese Medicine,Tianjin 301617,China [5]Department of Pharmacology,College of Pharmaceutical Sciences,Soochow University,Suzhou 215031,China [6]Key laboratory of Carcinogenesis and Cancer Invasion,Ministry of Education,Department of Pathology,Xiangya Hospital,School of Basic Medicine,Central South University,Changsha 410078,China [7]NHC Key laboratory of Carcinogenesis,Cancer Research Institute,Central South University,Changsha 410078,China

出　　处：《Acta Pharmacologica Sinica》2022年第6期1594-1604,共11页中国药理学报（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China under Grant Nos.81972480 and 21472138;National Science and Technology Major Project(2017ZX09301012);The Key Research and Development Program of Hunan Province(2019DK2011);Scientific Research Project of Hunan Provincial Health Commission(202102080940);Vemurafenib-resistant A-375 cells were a gift from Cong Peng,Xiangya Hospital,Central South University.

摘　　要：Physapubenolide(PB),a withanolide-type compound extracted from the traditional herb Physalis minima L.,has been demonstrated to exert remarkable cytotoxicity against cancer cells;however,its molecular mechanisms are still unclear.In this study,we demonstrated that PB inhibited cell proliferation and migration in melanoma cells by inducing cell apoptosis.The anticancer activity of PB was further verified in a melanoma xenograft model.To explore the mechanism underlying the anticancer effects of PB,we carried out an in silico target prediction study,which combined three approaches(chemical similarity searching,quantitative structure-activity relationship(QSAR),and molecular docking)to identify the targets of PB,and found that PB likely targets 3-hydroxy-methylglutaryl CoA reductase(HMGCR),the rate-limiting enzyme of the mevalonate pathway,which promotes cancer cell proliferation,migration,and metastasis.We further demonstrated that PB interacted with HMGCR,decreased its protein expression and inhibited the HMGCR/YAP pathway in melanoma cells.In addition,we found that PB could restore vemurafenib sensitivity in vemurafenib-resistant A-375 cells,which was correlated with the downregulation of HMGCR.In conclusion,we demonstrate that PB elicits anticancer action and enhances sensitivity to vemurafenib by targeting HMGCR.

关 键 词：physapubenolide melanoma cells HMGCR VEMURAFENIB drug resistance 

分 类 号：R739.5[医药卫生—肿瘤]