New Molecular and Biological Mechanism of Antitumor Activities of KW-2478, a Novel Nonansamycin Heat Shock Protein 90 Inhibitor, in Multiple Myeloma Cells
New Molecular and Biological Mechanism of Antitumor Activities of KW-2478, a Novel Nonansamycin Heat Shock Protein 90 Inhibitor, in Multiple Myeloma Cells
复制标题
DOI：
10.1158/1078-0432.ccr-09-3112
复制
发表时间：
2010-05-15
影响因子：
11.5
通讯作者：
Shiotsu, Yukimasa
中科院分区：
文献类型：
--
作者：
Nakashima, Takayuki;Ishii, Toshihiko;Shiotsu, Yukimasa
目的：热休克蛋白90（Hsp 90）在多发性骨髓瘤（MM）细胞中的致癌客户蛋白的陪伴中起重要作用，并且几种Hsp 90抑制剂在体外和体内都显示出抗肿瘤活性。然而，Hsp 90抑制剂在MM中的确切作用机制尚未完全阐明。实验设计：我们评估了KW-2478（nonansamycin Hsp 90抑制剂）在具有免疫球蛋白重链（IgH）基因座的各种染色体易位的MM细胞中的体外和体内抗肿瘤活性。我们的研究表明，KW-2478暴露于MM细胞导致生长抑制和凋亡，这与众所周知的客户蛋白的降解以及IgH易位产物的减少有关（FGFR 3、c-Maf和cyclin D1），并且FGFR 3被证明是Hsp 90伴侣复合物的新客户蛋白。此外，KW-2478耗尽了Hsp 90客户端Cdk 9（一种转录激酶）和磷酸化的4 E-BP 1（一种翻译抑制剂）。KW-2478对这种转录和翻译途径的抑制作用均显示出降低c-Maf和细胞周期蛋白D1的表达。在NCI-H929 s.c.在接种模型中，KW-2478显示出对肿瘤生长的显著抑制并诱导肿瘤中客户蛋白的降解。此外，在一个新的原位MM模型的静脉接种的OPM-2/绿色荧光蛋白，KW-2478显示了显着减少血清M蛋白和MM肿瘤负担在bone marrow.Conclusions：这些结果表明，针对这些不同的途径KW-2478可能是一个有前途的策略，用于治疗MM与各种细胞遗传学异常。临床癌症研究; 16（10）; 2792-802。(C)2010年AACR。
Purpose: The heat shock protein 90 (Hsp90) plays an important role in chaperoning oncogenic client proteins in multiple myeloma (MM) cells, and several Hsp90 inhibitors have shown antitumor activities both in vitro and in vivo. However the precise mechanism of action of Hsp90 inhibitor in MM has not been fully elucidated.Experimental Design: We evaluated the antitumor activities of KW-2478, a nonansamycin Hsp90 inhibitor, in MM cells with various chromosomal translocations of immunoglobulin heavy chain (IgH) loci both in vitro and in vivo.Results: Our studies revealed that exposure of KW-2478 to MM cells resulted in growth inhibition and apoptosis, which were associated with degradation of well-known client proteins as well as a decrease in IgH translocation products (FGFR3, c-Maf, and cyclin D1), and FGFR3 was shown to be a new client protein of Hsp90 chaperon complex. In addition, KW-2478 depleted the Hsp90 client Cdk9, a transcriptional kinase, and the phosphorylated 4E-BP1, a translational inhibitor. Both inhibitory effects of KW-2478 on such transcriptional and translational pathways were shown to reduce c-Maf and cyclin D1 expression. In NCI-H929 s.c. inoculated model, KW-2478 showed a significant suppression of tumor growth and induced the degradation of client proteins in tumors. Furthermore, in a novel orthotopic MM model of i.v. inoculated OPM-2/green fluorescent protein, KW-2478 showed a significant reduction of both serum M protein and MM tumor burden in the bone marrow.Conclusions: These results suggest that targeting such diverse pathways by KW-2478 could be a promising strategy for the treatment of MM with various cytogenetic abnormalities. Clin Cancer Res; 16(10); 2792-802. (C) 2010 AACR.