ADH-1 suppresses N-cadherin-dependent pancreatic cancer progression
ADH-1 suppresses N-cadherin-dependent pancreatic cancer progression
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DOI：
10.1002/ijc.23027
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发表时间：
2008-01-01
影响因子：
6.4
通讯作者：
Johnson，Keith R.
中科院分区：
文献类型：
--
作者：
Shintani，Yasushi;Fukumoto，Yuri;Johnson，Keith R.
胰腺癌是最具侵袭性的恶性疾病之一。我们最近报道了N-钙粘附素在胰腺癌的肿瘤进展和转移中起关键作用。在这项研究中，我们试图确定N-钙粘附素阻断肽(ADH-1)是否可以阻止N-钙粘附素介导的胰腺癌小鼠模型的肿瘤进展。以胰腺癌细胞为研究对象，观察ADH-1对N-钙粘素介导的细胞在I型胶原上的散射和迁移的影响。我们还检测了ADH-1对细胞凋亡的影响。此外，在活体动物研究中，使用原位注射高表达N-钙粘素的BxPC-3细胞，并加或不加ADH-1处理。BxPC-3和Capan-1细胞表现出对I型胶原反应的N-钙粘蛋白表达增加，这种增加促进了细胞对I型胶原反应的分散和迁移。ADH-1阻止了这些变化，但不抑制N-钙粘附素的上调。原位末端标记法和caspase-3免疫印迹分析显示ADH-1以浓度依赖和N-钙粘素依赖的方式诱导胰腺癌细胞的凋亡。ADH-1治疗显著减少了胰腺癌小鼠模型的肿瘤生长和肺转移。N-钙粘素拮抗剂ADH-1在体外试验和小鼠胰腺癌原位模型中对表达N-钙粘附素的细胞具有显著的抗肿瘤活性，增加了N-钙粘附素拮抗剂治疗人类胰腺癌的可能性。©2007 Wiley-Liss Inc.
Pancreatic cancer is one of the most aggressive malignant diseases. We recently reported that N‐cadherin plays a key role in tumor progression and metastasis in pancreatic cancer. For this study, we sought to determine if an N‐cadherin‐blocking peptide (ADH‐1) could prevent N‐cadherin‐mediated tumor progression in a mouse model for pancreatic cancer. The effect of ADH‐1 on N‐cadherin‐mediated cell scattering and migration on collagen I was examined using pancreatic cancer cells. We also examined the influence of ADH‐1 on cell apoptosis. Furthermore,in vivoanimal studies were performed using orthotopic injection of N‐cadherin overexpressing BxPC‐3 cells with or without ADH‐1 treatment. BxPC‐3 and Capan‐1 cells exhibited increased expression of N‐cadherin in response to collagen I. This increase in N‐cadherin promoted cell scattering and migration in response to collagen I. ADH‐1 prevented these changes, but did not inhibit upregulation of N‐cadherin. TUNEL assays and immunoblots for caspase‐3 showed that ADH‐1 induced apoptosis in a concentration dependent and N‐cadherin dependent manner in pancreatic cancer cells. ADH‐1 treatment resulted in significant reductions in tumor growth and lung metastasis in a mouse model for pancreatic cancer. The N‐cadherin antagonist, ADH‐1 has significant antitumor activity against N‐cadherin‐expressing cells usingin vitroassays and in an orthotopic mouse model for pancreatic cancer, raising the possibility that N‐cadherin antagonists have therapeutic potential for the treatment of pancreatic cancer in humans. © 2007 Wiley‐Liss, Inc.