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Title: Novel Hsp90 inhibitor platycodin D disrupts Hsp90/Cdc37 complex and enhances the anticancer effect of mTOR inhibitor

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. - Highlights: • Platycodin D (PD) is a novel Hsp90 inhibitor by disrupting Hsp90/Cdc37 complex. • PD terminated the survival signal induced by mTORmore » inhibition via feedback blockade. • Combining mTOR inhibitor and PD together exhibited amplified anti-NSCLC effect.« less

Authors:
;  [1];  [2];  [1];  [2]; ; ;  [1]; ;  [3];  [2];  [1]
  1. 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)
Publication Date:
OSTI Identifier:
22722913
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 330; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CELL DIVISION; COMPLEXES; FEEDBACK; GROWTH FACTORS; HEAT-SHOCK PROTEINS; INHIBITION; NEOPLASMS; PLANT GROWTH

Citation Formats

Li, Ting, Chen, Xin, Dai, Xiao-Yang, Wei, Bin, Weng, Qin-Jie, Chen, Xiuping, Ouyang, De-Fang, Yan, Ru, Huang, Zhang-Jian, Jiang, Hu-Lin, Zhu, Hong, and Lu, Jin-Jian. Novel Hsp90 inhibitor platycodin D disrupts Hsp90/Cdc37 complex and enhances the anticancer effect of mTOR inhibitor. United States: N. p., 2017. Web. doi:10.1016/J.TAAP.2017.07.006.
Li, Ting, Chen, Xin, Dai, Xiao-Yang, Wei, Bin, Weng, Qin-Jie, Chen, Xiuping, Ouyang, De-Fang, Yan, Ru, Huang, Zhang-Jian, Jiang, Hu-Lin, Zhu, Hong, & Lu, Jin-Jian. Novel Hsp90 inhibitor platycodin D disrupts Hsp90/Cdc37 complex and enhances the anticancer effect of mTOR inhibitor. United States. doi:10.1016/J.TAAP.2017.07.006.
Li, Ting, Chen, Xin, Dai, Xiao-Yang, Wei, Bin, Weng, Qin-Jie, Chen, Xiuping, Ouyang, De-Fang, Yan, Ru, Huang, Zhang-Jian, Jiang, Hu-Lin, Zhu, Hong, and Lu, Jin-Jian. Fri . "Novel Hsp90 inhibitor platycodin D disrupts Hsp90/Cdc37 complex and enhances the anticancer effect of mTOR inhibitor". United States. doi:10.1016/J.TAAP.2017.07.006.
@article{osti_22722913,
title = {Novel Hsp90 inhibitor platycodin D disrupts Hsp90/Cdc37 complex and enhances the anticancer effect of mTOR inhibitor},
author = {Li, Ting and Chen, Xin and Dai, Xiao-Yang and Wei, Bin and Weng, Qin-Jie and Chen, Xiuping and Ouyang, De-Fang and Yan, Ru and Huang, Zhang-Jian and Jiang, Hu-Lin and Zhu, Hong and Lu, Jin-Jian},
abstractNote = {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. - Highlights: • Platycodin D (PD) is a novel Hsp90 inhibitor by disrupting Hsp90/Cdc37 complex. • PD terminated the survival signal induced by mTOR inhibition via feedback blockade. • Combining mTOR inhibitor and PD together exhibited amplified anti-NSCLC effect.},
doi = {10.1016/J.TAAP.2017.07.006},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = ,
volume = 330,
place = {United States},
year = {2017},
month = {9}
}