Abstract
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.
Highlights
Heat shock protein (Hsp) 90 is a highly conserved chaperone protein and among the most abundant proteins found in eukaryotic cells [1,2,3]
As a novel Heat shock protein 90 (Hsp90) inhibitor, FW-04-806 binds to the N-terminal of Hsp90 and inhibits Hsp90/cell division cycle protein 37 (Cdc37) interaction, resulting in the disassociation of Hsp90/Cdc37/client complexes and the degradation of Hsp90 client proteins
FW-04-806 binds to the N-terminal of Hsp90 FW-04-806, extracted from the China-native Streptomyces FIM-04-806 and identical to Conglobatin [16], had been discovered to be one of the potential Hsp90 inhibitors in the initial screening (Figure 1A)
Summary
Heat shock protein (Hsp) 90 is a highly conserved chaperone protein and among the most abundant proteins found in eukaryotic cells [1,2,3]. Most Hsp client proteins, such as epidermal growth factor receptor 2 (HER2), Akt, Raf-1, Cdk, Bcr-Abl, and p53, are essential for cancer cell survival and proliferation [9]. The chaperoning of these client proteins is regulated by a dynamic cycle driven by ATP binding to Hsp and subsequent hydrolysis of the protein [10]. Hsp requires a series of co-chaperones to form a complex in order to function These co-chaperones, including cell division cycle protein 37 (Cdc37), Hsp, Hsp, Hop, Hip, p23, pp, and immunophilins, bind to the super-chaperone complex and are released at various time points to regulate the folding, assembly, and maturation of Hsp client proteins [11]. 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
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