Effect of Beta-secretase Inhibitors on Pancreatic Cancer Cells

描述（由申请人提供）：胰腺癌是美国癌症相关死亡的第四大常见原因，只有5%的确诊患者能存活根据开发胰腺癌新疗法的目标，我们建议扩大我们对β-分泌酶抑制剂和淀粉样蛋白受体样蛋白2（APLP 2）的研究。APLP 2是还包括淀粉样前体蛋白（APP）的蛋白质家族的成员。我们的初步数据显示，APLP 2在胰腺癌细胞系和人胰腺癌组织中充分表达。APLP 2在细胞表面以跨膜形式存在，其被β-分泌酶切割导致C-末端片段从分泌的N-末端结构域释放。β-分泌酶，也称为淀粉样前体蛋白裂解酶1和2（BACE 1和BACE 2），是跨膜天冬氨酸蛋白酶。几家公司正在开发β-分泌酶的抑制剂用于治疗阿尔茨海默病，因为除了切割APLP 2之外，β-分泌酶还切割APP，这是β-淀粉样蛋白（与阿尔茨海默病的病因学有关）产生的一个步骤。这类抑制剂在小鼠和人类中具有相对良好的安全性。在我们的初步研究中，我们发现用新型β-分泌酶抑制剂治疗会降低胰腺癌细胞的存活率。此外，我们已经表明，β-分泌酶切割淀粉样蛋白受体样蛋白2（APLP 2）是增加转化胰腺导管细胞，和β分泌酶切割APLP 2的抑制与胰腺癌细胞存活率降低。我们将检验的中心假设是β-分泌酶抑制剂阻断淀粉样蛋白受体样蛋白2（APLP 2）的切割，从而降低胰腺癌细胞的存活能力。本研究的完成将阐明β-分泌酶抑制剂抑制胰腺癌细胞生长的机制，并明确APLP 2在该机制中的重要性。这项研究的结果预计将支持β-分泌酶抑制剂作为胰腺癌新疗法的未来转化和临床研究。此外，除了它们的翻译潜力，这些研究有望为胰腺癌细胞存活的基本分子调控提供新的视角。

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth most frequent cause of cancer-related death in the U.S., and only about 5% of patients diagnosed with this disease survive. Pursuant to the goal of developing new treatments for pancreatic cancer, we propose to expand our studies on beta-secretase inhibitors and amyloid precursor-like protein 2 (APLP2). APLP2 is a member of a family of proteins that also includes amyloid precursor protein (APP). Our preliminary data show that APLP2 is amply expressed in pancreatic cancer cell lines and human pancreatic cancer tissues. APLP2 is found in transmembrane form at the cell surface, and its cleavage by beta-secretases leads to the release of C-terminal fragments from a secreted N-terminal domain. Beta-secretases, also called ¿-site amyloid precursor protein cleaving enzyme 1 and 2 (BACE1 and BACE2), are transmembrane aspartic proteases. Inhibitors of beta-secretases are in development for the treatment of Alzheimer's disease by several companies, because in addition to cleaving APLP2 the beta-secretases also cleave APP, which is a step in the production of beta-amyloid (implicated in the etiology of Alzheimer's disease). Such inhibitors have a relatively good safety profile in mice and humans. In our preliminary studies, we have found that treatment with novel beta-secretase inhibitors reduces pancreatic cancer cell survival. Furthermore, we have shown that beta-secretase cleavage of amyloid precursor-like protein 2 (APLP2) is increased in transformed pancreatic ductal cells, and that inhibition of beta secretase cleavage of APLP2 correlates with reduced pancreatic cancer cell survival. The central hypothesis that we will test is that beta-secretase inhibitors block the cleavage of amyloid precursor-like protein 2 (APLP2), and thereby reduce the ability of pancreatic cancer cells to survive. Accomplishment of this project will elucidate the mechanism underlying the ability of beta- secretase inhibitors to decrease pancreatic cancer cell growth, and define the importance of APLP2 to the mechanism. The results from this study are anticipated to support future translational and clinical studies of beta-secretase inhibitors as novel therapies for pancreatic cancer. Furthermore, in addition to their translational potential, these studies are expected to provide new perspectives on the basic molecular regulation of pancreatic cancer cell survival.