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Novel Hsp90 inhibitor platycodin D disrupts Hsp90/Cdc37 complex and enhances the anticancer effect of mTOR inhibitor
Li, Ting1; Chen, Xin1; Dai, Xiao-Yang2; Wei, Bin1; Weng, Qin-Jie2; Chen, Xiuping1; Ouyang, De-Fang1; Yan, Ru1; Huang, Zhang-Jian3; Jiang, Hu-Lin3; Zhu, Hong2; Lu, Jin-Jian1
2017-09
Source PublicationTOXICOLOGY AND APPLIED PHARMACOLOGY
ISSN0041-008X
Volume330Pages:65-73
Abstract

Heat shock protein 90 (Hsp90) is a critically conserved molecular chaperone protein and promising therapeutic target for cancer treatment. In this study, platycodin D (PD), a saponin isolated from traditional Chinese herb Platycodonis Radix, was identified as a novel Hsp90 inhibitor. We verified that PD did not affect the ATPase activity of Hsp90. However, PD disrupted the co-chaperone interaction of Hsp90/cell division cycle protein 37 (Cdc37) and subsequently degraded multiple Hsp90 client proteins without the feedback increase of Hsp70. In different genotypes of non -small cell lung cancer cells, co-treatment with the mTOR inhibitor Everolimus and PD enhanced antiproliferation activity and apoptotic effect. The feedback survival signal upon mTOR inhibition was fully terminated by the co-administration with PD through reduced epidermal growth factor receptor (EGFR) and insulin growth factor 1 receptor (IGF1R) expression, suppressed AKT activity, and reinforced 4E-BP1 inhibition. Our results not only identified PD as a novel Hsp90 inhibitor by disrupting the protein-protein interaction of Hsp90/Cdc37 complex, but also provided mechanistic insights into the ineffectiveness of mTOR inhibitors and identified therapeutic strategy for cancer treatment. (C) 2017 Elsevier Inc. All rights reserved.

KeywordEverolimus Platycodin d Hsp90 Cdc37 Egfr Igf1r
DOI10.1016/j.taap.2017.07.006
URLView the original
Indexed BySCI
Language英语
WOS Research AreaPharmacology & Pharmacy ; Toxicology
WOS SubjectPharmacology & Pharmacy ; Toxicology
WOS IDWOS:000407662600008
PublisherACADEMIC PRESS INC ELSEVIER SCIENCE
The Source to ArticleWOS
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Cited Times [WOS]:8   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
2.College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
3.State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
First Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Li, Ting,Chen, Xin,Dai, Xiao-Yang,et al. Novel Hsp90 inhibitor platycodin D disrupts Hsp90/Cdc37 complex and enhances the anticancer effect of mTOR inhibitor[J]. TOXICOLOGY AND APPLIED PHARMACOLOGY,2017,330:65-73.
APA Li, Ting.,Chen, Xin.,Dai, Xiao-Yang.,Wei, Bin.,Weng, Qin-Jie.,...&Lu, Jin-Jian.(2017).Novel Hsp90 inhibitor platycodin D disrupts Hsp90/Cdc37 complex and enhances the anticancer effect of mTOR inhibitor.TOXICOLOGY AND APPLIED PHARMACOLOGY,330,65-73.
MLA Li, Ting,et al."Novel Hsp90 inhibitor platycodin D disrupts Hsp90/Cdc37 complex and enhances the anticancer effect of mTOR inhibitor".TOXICOLOGY AND APPLIED PHARMACOLOGY 330(2017):65-73.
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