Platycodin D, a novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex, enhances the anti-cancer effect of mTOR inhibitor

UM > Institute of Chinese Medical Sciences

Status	已發表Published
	Platycodin D, a novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex, enhances the anti-cancer effect of mTOR inhibitor
	Li, T; Chen, X; Dai, XY; Wei, B; Weng, QJ; Chen, X. P.; Ouyang, D.; Yan, R.; Huang, ZJ; Jiang, HL; Zhu, H; Lu, J.
	2017-08-01
Source Publication	16th Meeting of Consortium for Globalization of Chinese Medicine
Abstract	Heat shock protein (Hsp) 90 is a critical conserved molecular chaperone protein and promising therapeutic target for cancer treatment. Platycodin D (PD), a saponin isolated from traditional Chinese herb Platycodonis Radix, was identified as a novel heat shock protein (Hsp) 90 inhibitor. PD inhibited Hsp90 activity through disrupting the Hsp90/cell division cycle protein 37 (Cdc37) cochaperone interaction, instead of affecting ATP binding to Hsp90. The inhibition of Hsp90 by PD resulted in the degradation of multiple Hsp90 client proteins without feedback increase of Hsp70. Besides, PD could enhance the anticancer effect of the well-established mTOR inhibitors Everolimus, triggering an enhanced and apoptotic effect with reduced mitochondrial membrane potential and reinforced caspase 3/7 activities. We have verified that Everolimus caused a survival feedback signal as evidenced by increase of EGFR and IGF1R at both mRNA and protein levels, and pronounced activation of AKT. PD abolished Everolimus-mediated feedback survival signal via reduced EGFR and IGF1R expression, AKT activity, and reinforced 4E-BP1 inhibition. Taken together, we identified PD as a novel Hsp90 inhibitor by disrupting protein-protein interaction of Hsp90 and its chaperone Cdc37 for the first time. Our findings also found that the combination of mTOR inhibitor and the novel Hsp90 inhibitor PD overcomes the feedback activation of the RTKs/AKT pathway and leads to blockage of downstream survival signal, providing mechanistic insights into the ineffectiveness of mTOR inhibitors and identify implemented therapeutic strategy for NSCLC treatment.
Keyword	Everolimus platycodin D Hsp90 Cdc37 EGFR IGF1R
Language	英語English
The Source to Article	PB_Publication
PUB ID	34442
Document Type	Conference paper
Collection	Institute of Chinese Medical Sciences
Corresponding Author	Lu, J.
Recommended Citation GB/T 7714	Li, T,Chen, X,Dai, XY,et al. Platycodin D, a novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex, enhances the anti-cancer effect of mTOR inhibitor[C], 2017.
APA	Li, T., Chen, X., Dai, XY., Wei, B., Weng, QJ., Chen, X. P.., Ouyang, D.., Yan, R.., Huang, ZJ., Jiang, HL., Zhu, H., & Lu, J. (2017). Platycodin D, a novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex, enhances the anti-cancer effect of mTOR inhibitor. 16th Meeting of Consortium for Globalization of Chinese Medicine.

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