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.
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.
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FW-04-806 通过与 Hsp90 N 末端结合并破坏 Hsp90-Cdc37 复合物形成来抑制人乳腺癌细胞增殖并诱导细胞凋亡
DOI：
10.1186/1476-4598-13-150
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发表时间：
2014-06-14
期刊：
影响因子：
37.3
通讯作者：
Zheng W
中科院分区：
文献类型：
--
作者：
Huang W;Ye M;Zhang LR;Wu QD;Zhang M;Xu JH;Zheng W
热休克蛋白90（Heat shock protein 90，Hsp 90）是一个很有前途的治疗靶点，抑制Hsp 90可能导致多种信号通路的抑制。FW-04-806是从中国产链霉菌Streptomycescens-04-806中分离得到的一种双恶唑基大环内酯类化合物，其结构与聚酮Conglobatin相同。方法采用化学蛋白质组学、计算对接、免疫沉淀、siRNA基因敲除、实时定量PCR和异种移植模型等方法对FW-04-806的抗肿瘤机制进行研究，结果FW-04 - 806可直接与Hsp 90的N-末端结合，并可抑制Hsp 90/细胞分裂周期蛋白37（Cdc 37）伴侣/共-Hsp 90/细胞分裂周期蛋白37（Cdc 37）伴侣/共-Hsp 90蛋白的结合。分子伴侣相互作用，但不影响Hsp 90的ATP结合能力，从而导致多种Hsp 90客户蛋白通过蛋白酶体途径降解。在乳腺癌细胞系中，FW-04-806以剂量和时间依赖性方式抑制细胞增殖，引起G2/M细胞周期停滞，诱导细胞凋亡，并下调Hsp 90客户蛋白HER 2、Akt、Raf-1及其磷酸化形式（p-HER 2、p-Akt）。重要的是，FW-04-806在HER 2过表达的SKBR 3肿瘤异种移植模型中显示出比在HER 2低表达的MCF-7模型中更好的抗肿瘤作用。结果与SKBR-3和MCF-7的细胞增殖实验和体外凋亡实验一致。结论FW-04-806作为一种新型的Hsp 90抑制剂，可与Hsp 90的N端结合，抑制Hsp 90/Cdc 37相互作用，导致Hsp 90/Cdc 37/客户复合物解离，降解Hsp 90客户蛋白。FW-04-806在体外和体内均显示出良好的抗乳腺癌细胞活性，尤其是对HER 2过表达的乳腺癌细胞。
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-nativeStreptomycesFIM-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 andin vitroapoptosis 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 bothin vitroandin vivo, especially for HER2-overexpressed breast cancer cells.
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影响因子：
16.6
作者：
Sreeramulu, Sridhar;Gande, Santosh Lakshmi;Schwalbe, Harald
通讯作者：
Schwalbe, Harald
影响因子：
3.5
作者：
Falsone, SF;Gesslbauer, B;Kungl, AJ
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影响因子：
2.9
作者：
Rowlands, MG;Newbatt, YM;Aherne, W
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DOI：
10.1016/j.jnutbio.2011.11.004
发表时间：
2012-12
期刊：
The Journal of nutritional biochemistry
影响因子：
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作者：
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通讯作者：
Sun D
影响因子：
7
作者：
Fonovic, Marko;Verhelst, Steven H. L.;Bogyo, Matthew
通讯作者：
Bogyo, Matthew