FW-04-806 inhibits proliferation and induces apoptosis in human breast cancer cells by binding to N-terminus of Hsp90 and disrupting Hsp90-Cdc37 complex formation

Molecular Cancer

Research

Qun-dan Wu¹  Min Zhang¹  Jian-hua Xu²  Min Ye²  Wei Zheng³  Wei Huang³  Lian-ru Zhang⁴ 

[1] School of Pharmacy, Fujian Medical University, Basic Medicine Building North 205, No.88 Jiaotong Road, 350004, Fuzhou, Fujian, China;School of Pharmacy, Fujian Medical University, Basic Medicine Building North 205, No.88 Jiaotong Road, 350004, Fuzhou, Fujian, China;Fuijan Provincial Key Laboratory of Natural Medicine Pharmacology, 350004, Fuzhou, China;School of Pharmacy, Fujian Medical University, Basic Medicine Building North 205, No.88 Jiaotong Road, 350004, Fuzhou, Fujian, China;Fujian Institute of Microbiology, 350007, Fuzhou, China;School of life Sciences, Xiamen University, 361005, Xiamen, China;

关键词: FW-04-806;    Hsp90;    Cdc37;    HER2;    Breast cancer;   

DOI  :  10.1186/1476-4598-13-150

 received in 2014-01-15, accepted in 2014-06-05,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundHeat shock protein 90 (Hsp90) is a promising therapeutic target and inhibition of Hsp90 will presumably result in suppression of multiple signaling pathways. FW-04-806, a bis-oxazolyl macrolide compound extracted from China-native Streptomyces FIM-04-806, was reported to be identical in structure to the polyketide Conglobatin.MethodsWe adopted the methods of chemproteomics, computational docking, immunoprecipitation, siRNA gene knock down, Quantitative Real-time PCR and xenograft models on the research of FW-04-806 antitumor mechanism, through the HER2-overexpressing breast cancer SKBR3 and HER2-underexpressing breast cancer MCF-7 cell line.ResultsWe have verified the direct binding of FW-04-806 to the N-terminal domain of Hsp90 and found that FW-04-806 inhibits Hsp90/cell division cycle protein 37 (Cdc37) chaperone/co-chaperone interactions, but does not affect ATP-binding capability of Hsp90, thereby leading to the degradation of multiple Hsp90 client proteins via the proteasome pathway. In breast cancer cell lines, FW-04-806 inhibits cell proliferation, caused G2/M cell cycle arrest, induced apoptosis, and downregulated Hsp90 client proteins HER2, Akt, Raf-1 and their phosphorylated forms (p-HER2, p-Akt) in a dose and time-dependent manner. Importantly, FW-04-806 displays a better anti-tumor effect in HER2-overexpressed SKBR3 tumor xenograft model than in HER2-underexpressed MCF-7 model. The result is consistent with cell proliferation assay and in vitro apoptosis assay applied for SKBR-3 and MCF-7. Furthermore, FW-04-806 has a favorable toxicity profile.ConclusionsAs a novel Hsp90 inhibitor, FW-04-806 binds to the N-terminal of Hsp90 and inhibits Hsp90/Cdc37 interaction, resulting in the disassociation of Hsp90/Cdc37/client complexes and the degradation of Hsp90 client proteins. FW-04-806 displays promising antitumor activity against breast cancer cells both in vitro and in vivo, especially for HER2-overexpressed breast cancer cells.

【 授权许可】

Unknown   
© Huang et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.