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Increased Expression and Processing of the Alzheimer Amyloid Precursor Protein in Pancreatic Cancer May Influence Cellular Proliferation

Departments of Pathology [D. E. H., A. R., A. M.], Surgery [C. J. Y.], and Oncology [C. J. Y.], The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and the Institute of Cell Biology and Bonner Forum Biomedizin, University of Bonn, D-53115 Bonn, Germany [S. W., V. H.]

Abnormal cleavage of amyloid precursor protein (APP) in the central nervous system has been linked to the development of Alzheimer’s disease. Recent work has identified additional roles for APP in peripheral tissue, such as cellular proliferation and motility. APP undergoes proteolytic processing to release a soluble NH₂-terminal ectodomain fragment (sAPP), an Aß or p3 peptide, and cytosolic COOH-terminal fragments. We have identified the up-regulation of APP expression in pancreatic cancer cells both in vitro and in vivo. APP undergoes high levels of proteolytic processing in pancreatic cancer cells, and sAPP can be detected in collected medium in vitro. Inhibition of sAPP signaling reduces pancreatic cancer cell number via a reduction in cellular proliferation. We propose that APP may function to promote growth in pancreatic cancer cells via signaling through sAPP and may therefore represent a novel therapeutic target in pancreatic cancer.

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