Abstract 4010: Role of ADAM10-mediated APP processing in pancreatic cancer.

Abstract

Abstract Pancreatic cancer is the fourth leading cause of cancer-related death in United States and is characterized by poor prognosis and low survival rate. Current chemotherapeutic interventions include drugs such as Gemcitabine which can prolong the survival only marginally and hence it is important that new molecular targets be identified for early detection and drug development for more effective treatment of this cancer. Recent studies have shown that Amyloid Precursor Protein (APP), a protein mainly studied in association with pathogenesis of Alzheimer's disease (AD), is overexpressed in human pancreatic cancer raising the possibility that it may be involved in oncogenesis. APP is processed by different proteases and secretases to give rise to fragments with different functional properties. Certain proteolytic fragments of APP are known to cause neuronal apoptosis, as in AD, while other fragments exhibit growth promoting and anti-apoptotic properties. The molecular mechanisms by which APP or fragments of APP induce cell proliferation or oncogenesis has not been elucidated. One of the proteolytic fragments of APP that exhibits growth promoting characteristics is the secreted APP alpha (sAPPα). The major enzyme that mediates APP cleavage to generate sAPPα has been identified as ADAM10, which belongs to the ADAM (a disintegrin and metalloprotease) family of proteases. ADAM10 expression is elevated in pancreatic cancer but the functional significance of this upregulation is not known. Based on the role of this enzyme in generation of the pro-proliferative sAPPα, we hypothesize that ADAM10 promotes pancreatic cancer progression through regulation of APP. Our studies show that CD18, MiaPaCa2 and Panc1 pancreatic cancer cells overexpress APP as well as ADAM10. In order to determine whether inhibition of ADAM10 has an effect on generation of sAPPα, we treated these cells with Batimastat, a known inhibitor of ADAM10. We found that Batimastat significantly inhibits sAPPα generation, with concomitant reduction in cell proliferation as well as anchorage-independent growth of colonies in soft agar. Interestingly, this inhibitory effect is enhanced when cells are treated with a combination of Batimastat and Gemcitabine suggesting that Batimastat sensitizes the cells to Gemcitabine. In vitro addition of recombinant sAPPα could rescue the inhibitory effect of Batimastat thereby suggesting that ADAM10 is promoting the proliferation of pancreatic cancer cells through the generation of sAPPα. This was further supported by knock down studies using siRNA targeting APP. Cytotoxicity assay with APP knock down cells showed a significant reduction in cell viability which was comparable to cells treated with Batimastat. These results suggest that inhibitors of sAPPα generation can enhance the therapeutic potential of the established pancreatic cancer treatment regimen and help improve the prognosis of cancer patients. Citation Format: Neha Woods, Jaya Padmanabhan. Role of ADAM10-mediated APP processing in pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4010. doi:10.1158/1538-7445.AM2013-4010