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FW-04-806 inhibits proliferation and induces apoptosis in human breast cancer cells by binding to N-terminus ofHsp90 and disrupt

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FW-04-806 inhibits proliferation and induces apoptosis in human breast cancer cells by binding to N-terminus ofHsp90 and disrupt

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作者
Huang W, Ye M, Zhang LR, Wu QD, Zhang M, Xu JH, Zheng W.
刊物名称
Mol Cancer.
2014
Online
Online

  {Author}:Huang W, Ye M, Zhang LR, Wu QD, Zhang M, Xu JH, Zheng W.

  {Year}:2014

  {Title}:FW-04-806 inhibits proliferation and induces apoptosis in human breast cancer cells by binding to N-terminus ofHsp90 and disrupting Hsp90-Cdc37 complex formation.

  {Journal}:Mol Cancer.

  {Volume}: Online

  {Pages}:online

  {Keywords}:FW-04-806, Hsp90, Cdc37, HER2, Breast cancer

  {Abstract}:

  BACKGROUND:

  Heat 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.

  METHODS:

  We 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.

  RESULTS:

  We 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.

  CONCLUSIONS:

  As 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.

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