ADH-1 suppresses N-cadherin-dependent pancreatic cancer progression

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 vivo animal 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 using in vitro assays 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.