Early Detection Research Network

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.

Chaika N, Fukumoto Y, Grandgenett PM, Hollingsworth MA, Johnson KR, Shintani Y, Wheelock MJ

17721921

Int. J. Cancer, 2008, 122 (1)

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