Targeting heat-shock protein 90 with ganetespib for molecularly targeted therapy of gastric cancer.
Targeting heat-shock protein 90 with ganetespib for molecularly targeted therapy of gastric cancer.
复制标题
用ganetespib靶向热休克蛋白90用于胃癌的分子靶向治疗
DOI：
10.1038/cddis.2014.555
复制
发表时间：
2015-01-15
影响因子：
9
通讯作者：
Tu Z
中科院分区：
文献类型：
--
作者：
Liu H;Lu J;Hua Y;Zhang P;Liang Z;Ruan L;Lian C;Shi H;Chen K;Tu Z
胃癌（GC）仍然是全球第五大常见癌症。热休克蛋白90（Heat-shockprotein 90，HSP 90）在肿瘤组织中的异常高表达，使其成为肿瘤治疗的重要靶点。几个能够抑制GC的HSP 90抑制剂的成功案例启发我们尝试ganetespib，这是一种临床上有前途且正在积极研究的第二代HSP 90抑制剂用于GC治疗。在我们的研究中，我们表明ganetespib显著降低了MGC-803的生长，并以剂量依赖性方式显著抑制了SGC-7901和MKN-28的生长。诱导G2/M期细胞阻滞和细胞凋亡，并对相关标志物产生显著影响。机制上，ganetespib引起经典HSP 90客户蛋白表达的显著降低。具体而言，它通过显著降低总EGFR和细胞膜上EGFR的水平，极大地影响了表皮生长因子受体（EGFR）信号级联。EGFR基因敲低还诱导细胞周期停滞和凋亡，伴随着几种EGFR下游蛋白的减少。这些结果强烈支持EGFR信号传导对ganetespib抑制作用有很大贡献。此外，我们发现GC细胞系对ganetespib的反应与其EGFR表达水平密切相关：EGFR表达较高的MGC-803以及AGS和BGC-803对ganetespib的反应更好，而EGFR水平较低的SGC-7901和MKN-28对ganetespib的敏感性要低得多。虽然SGC-7901和MKN-28对ganetespib不是很敏感，但ganetespib与放射和顺铂协同作用杀死它们。重要的是，ganetespib作为单一药物或与顺铂组合在体内显著抑制异种移植肿瘤的生长。苏木精/伊红染色、TUNEL（末端脱氧核苷酸转移酶dUTP缺口末端标记）测定和磷酸化细胞周期蛋白依赖性激酶1（pCDK 1）、EGFR和Ki-67的免疫组织化学染色结果显示，ganetespib治疗的肿瘤存在显著差异。总的来说，我们的数据表明，ganetespib，作为一种新的有效的治疗选择，可用于胃癌患者的EGFR表达谱的分子靶向治疗。
Gastric cancer (GC) remains the fifth most common cancer worldwide. Heat-shock protein 90 (HSP90) has become an attractive therapeutic target in treating cancers, because of its abnormally high expression in cancers. Several successful cases of HSP90 inhibitors capable of inhibiting GC inspired us to try ganetespib, a clinically promising and actively investigated second-generation HSP90 inhibitor in GC treatment. In our study, we show that ganetespib markedly reduced the growth of MGC-803 and also significantly inhibited the growth of SGC-7901 and MKN-28 in a dose-dependent manner. It induced G2/M cell-cycle arrest and apoptosis in all three cell lines, together with the related markers affected significantly. Mechanistically, ganetespib caused pronounced decrease of expression of classic HSP90 client proteins. Specifically, it greatly affected epidermal growth factor receptor (EGFR) signaling cascades by markedly decreasing the levels of total EGFR and EGFR on cell membranes. EGFR knockdown also induced cell-cycle arrest and apoptosis accompanied with a decrease of several EGFR downstream proteins. These results strongly support that EGFR signaling greatly contributes to the ganetespib inhibitory effects. Besides, we found that the responses of GC cell lines to ganetespib correlated well with their EGFR expression levels: MGC-803, as well as AGS and BGC-803, with higher EGFR expression responded to ganetespib better, whereas SGC-7901 and MKN-28 with lower EGFR levels were much less sensitive to ganetespib. Although SGC-7901 and MKN-28 were not very sensitive to ganetespib, ganetespib worked synergistically with radiation and cisplatin in killing them. Importantly, ganetespib significantly inhibited the growth of xenograft tumors in vivo as a single agent or in combination with cisplatin. Results of hematoxylin/eosin staining, TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) assays, and immunohistochemistry staining of phosphorylated cyclin-dependent kinase 1 (pCDK1), EGFR and Ki-67 revealed significant differences in ganetespib-treated tumors. Collectively, our data suggest that ganetespib, as a new potent treatment option, can be used for the molecularly targeted therapy of GC patients according to their expression profiles of EGFR.