Alterations in Gene Expression in Pancreatic Cancer Cell Lines Induced by the N-terminal Fragment of APP (sAPP). Free

211

The Alzheimer amyloid precursor protein (APP) undergoes proteolytic processing to release a soluble NH₂-terminal ectodomain fragment (sAPP), an AΒ or p3 peptide, and cytosolic COOH-terminal fragments. Recent work has identified that APP is expressed in pancreatic cancer specimens and application of sAPP to pancreatic cancer cell lines in vitro can promote robust cellular proliferation (Hansel et al, Cancer Res, 2003). We have utilized the Affymetrix U133v2 GeneChip to examine global gene expression profiles from BxPC3 pancreatic cancer cell lines (American Type Culture Colection cell line bank, Manassas,VA) treated with 16 nM sAPP versus control medium. Microarray hybridization data were normalized using Affymetrix MAS to identify differentially over- and underexpressed genes in cells treated with sAPP. Addition of 16 nM sAPP induced an increase in cellular proliferation of 38% over cells treated with control medium. Utilizing a twofold change in gene expression, we have identified 59 overexpressed and 130 underexpresed genes in cells treated with 16 nM sAPP. Several classes of genes were altered by more than threefold and included described oncogenes and transcription factors (JUN, ETS), DNA helicases (RECQL5), pharmacologic mediators (CYP3A4), p53 antagonists (MDM2) and downstream mediators of the Rho/Rac signaling pathway (PAK2) were overexpressed in cells treated with sAPP. Underexpressed genes included putative Rb and p53 interactors (GAS1), transcription factors (POU3F1, KLF13), and chemotherapeutic sensitizing molecules (TP53I11). Several signaling pathways identified by this study have been implicated in pancreatic carcinogenesis and metastases, including the CDKN1A, neurokinin, and prostaglandin pathways. This is the first study to ascribe a potential oncogenic role to APP, and identify putative downstream targets that mediate these effects in pancreatic cancer.