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.

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

Department of Pharmacy,The Second Xiangya Hospital,Central South University,Changsha 410011,China;Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug,Changsha 410011,China;Xiangya School of Pharmaceutical Sciences,Central South University,Changsha 410008,China;School of Chinese Materia Medica and Tianjin State Key Laboratory of Modern Chinese Medicine,Tianjin University of Traditional Chinese Medicine,Tianjin 301617,China;Department of Pharmacology,College of Pharmaceutical Sciences,Soochow University,Suzhou 215031,China;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;NHC Key laboratory of Carcinogenesis,Cancer Research Institute,Central South University,Changsha 410078,China

中国药理学报（英文版）

[1]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-.Identification of HMGCR as the anticancer target of physapubenolide against melanoma cells by in silico target prediction)[J].中国药理学报（英文版）,2022(06):1594-1604

physapubenolide,Physapubenolide,withanolide,Physalis

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