Inhibition of heat shock protein 90 impairs epidermal growth factor-mediated signaling in gastric cancer cells and reduces tumor growth and vascularization in vivo
Inhibition of heat shock protein 90 impairs epidermal growth factor-mediated signaling in gastric cancer cells and reduces tumor growth and vascularization in vivo
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DOI：
10.1158/1535-7163.mct-06-0628
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发表时间：
2007-03-01
影响因子：
5.7
通讯作者：
Stoeltzing, Oliver
中科院分区：
文献类型：
--
作者：
Lang, Sven A.;Klein, Dagmar;Stoeltzing, Oliver
通过表皮生长因子受体（EGFR）、HER-2和缺氧诱导因子-1 α（HIF-1 α）的活化的致癌信号传导已通过上调血管内皮生长因子（VEGF）而与胃癌生长和血管生成有关。最近，热休克蛋白90（Hsp 90）已被确定为致癌蛋白稳定性的关键调节因子，包括EGFR，HER-2和HIF-1 α。我们推测抑制Hsp 90会损害胃癌细胞中EGF和低氧介导的血管生成信号，从而抑制血管生成和肿瘤生长。在体外，格尔德霉素衍生物17-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG）导致细胞外信号调节激酶1/2，Akt和信号转导和转录激活因子3的组成性和诱导性激活显著减少，并减少核HIF-1 α蛋白。此外，EGFR和HER-2在Hsp 90抑制后下调。关于血管生成分子的调节，17-AAG显著降低EGF介导的VEGF分泌。粘着斑激酶和桩蛋白的磷酸化均被17-AAG废除，这导致癌细胞运动性的显著损害。有趣的是，17-AAG在体外对癌细胞和胃成纤维细胞的细胞毒性作用高于对周细胞的作用。在体内，水溶性化合物17-二甲基氨基乙基氨基-17-去甲氧基格尔德霉素（17-DMAG; 25 mg/kg，每周三次）显著降低了s.c.异种移植肿瘤生长。通过免疫组织化学，17-DMAG显著减少切片中的血管面积和增殖肿瘤细胞的数量。此外，当以低剂量治疗（5 mg/kg，每周三次）给药时，17-DMAG达到了类似的显著生长抑制作用。总之，阻断Hsp 90破坏了胃癌细胞中的多种促血管生成信号通路，并抑制了体内异种移植肿瘤的生长。因此，胃癌具有用Hsp 90抑制剂治疗的有吸引力的分子靶点，这可能导致改善的Hsp 90治疗方案的功效。
Oncogenic signaling through activation of epidermal growth factor receptor (EGFR), HER-2, and hypoxia inducible-factor-1 alpha (HIF-1 alpha) has been implicated in gastric cancer growth and angiogenesis through upregulation of vascular endothelial growth factor (VEGF). Recently, heat shock protein 90 (Hsp90) has been identified as a critical regulator of oncogenic protein stability, including EGFR, HER-2, and HIF-1 alpha. We hypothesized that inhibition of Hsp90 impairs EGF- and hypoxiamediated angiogenic signaling in gastric cancer cells and consequently inhibits angiogenesis and tumor growth. In vitro, the geldanamycin derivate 17-allylamino-17-demethoxygeldanamycin (17-AAG) led to marked reduction in constitutive and inducible activation of extracellular signal-regulated kinase 1/2, Akt, and signal transducer and activator of transcription 3 and decreased nuclear HIF-1 alpha protein. In addition, EGFR and HER-2 were down-regulated after Hsp90 inhibition. With respect to regulation of angiogenic molecules, 17-AAG significantly reduced EGF-mediated VEGF secretion. Phosphorylation of focal adhesion kinase and paxillin were both abrogated by 17-AAG, which resulted in significant impairment of cancer cell motility. Interestingly, cytotoxic effects of 17-AAG in vitro were higher on cancer cells and gastric fibroblasts than on pericytes. In vivo, the water-soluble compound 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG; 25 mg/kg, thrice per week) significantly reduced s.c. xenografted tumor growth. By immunohistochemistry, 17-DMAG significantly reduced vessel area and numbers of proliferating tumor cells in sections. Furthermore, similar significant growth-inhibitory effects of 17-DMAG were achieved when administered as low-dose therapy (5 mg/kg, thrice per week). In conclusion, blocking Hsp90 disrupts multiple proangiogenic signaling pathways in gastric cancer cells and inhibits xenografted tumor growth in vivo. Hence, gastric cancer harbors attractive molecular targets for therapy with Hsp90 inhibitors, which could lead to improved efficacy of antineoplastic therapy regimens.