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，只有约5%的被诊断患有这种疾病的患者存活。根据开发胰腺癌新疗法的目标，我们建议扩大β -分泌酶抑制剂和淀粉样蛋白前体样蛋白2 （APLP2）的研究。APLP2是淀粉样蛋白前体蛋白（APP）家族中的一员。我们的初步数据显示，APLP2在胰腺癌细胞系和人胰腺癌组织中大量表达。APLP2以跨膜形式存在于细胞表面，β -分泌酶对其进行裂解，导致c端片段从分泌的n端区域释放出来。β -分泌酶，也称为-位点淀粉样蛋白前体切割酶1和2 (BACE1和BACE2)，是跨膜天冬氨酸蛋白酶。几家公司正在开发用于治疗阿尔茨海默病的β -分泌酶抑制剂，因为β -分泌酶除了可以切割APLP2外，还可以切割APP，这是β -淀粉样蛋白产生的一个步骤（与阿尔茨海默病的病因有关）。这类抑制剂在小鼠和人类中具有相对较好的安全性。在我们的初步研究中，我们发现使用新型β -分泌酶抑制剂治疗可降低胰腺癌细胞存活率。此外，我们已经证明β -分泌酶切割淀粉样前体样蛋白2 （APLP2）在转化的胰腺导管细胞中增加，抑制β -分泌酶切割APLP2与降低胰腺癌细胞存活率相关。我们将验证的中心假设是β -分泌酶抑制剂阻断淀粉样蛋白前体样蛋白2 （APLP2）的裂解，从而降低胰腺癌细胞的存活能力。本项目的完成将阐明β -分泌酶抑制剂抑制胰腺癌细胞生长的机制，并明确APLP2在这一机制中的重要性。这项研究的结果有望支持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，这些研究除了具有翻译潜力外，还有望为胰腺癌细胞生存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. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is an insidious and deadly illness. We have some evidence that available drugs, called beta-secretase inhibitors, kill pancreatic cancer cells. In this project, we will study how they are killing the cells, and this information will help in th fight to develop better treatments for pancreatic cancer patients.