The Role of MUC1 in the Pathogenesis of Pancreatic Cancer

MUC1在胰腺癌发病机制中的作用

• 批准号: 7684816
• 负责人: ASHOK K SALUJA
• 金额: $ 16.99万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7684816
• 关键词: Apoptosis; Apoptotic; Basic Science; Biological; C-Peptide; Cancer Etiology; Cancer cell line; Cathepsins; Cell Death; Cells; Cessation of life; Cytosol; Development; Diagnostic Neoplasm Staging; Disease; Down-Regulation; Enzymes; Heat shock proteins; Heat-Shock Proteins 70; Human; In Vitro; Laboratories; Lead; Lesion; Lysosomes; Malignant Neoplasms; Malignant neoplasm of pancreas; Membrane; Mitochondria; Molecular; Molecular Chaperones; Mucin-1 Staining Method; Mucins; Neoplasm Metastasis; Outcome; Pancreatic Intraepithelial Neoplasia; Pancreatic duct; Pathogenesis; Patients; Peptides; Permeability; Physiological; Play; Process; Property; Regulation; Role; Severities; Specimen; Staging; TNM; Testing; Therapeutic; Tumor stage; United States; base; cancer cell; cancer therapy; chemotherapeutic agent; cytochrome c; design; effective therapy; in vivo; mouse model; novel; overexpression; pancreatic neoplasm; prevent; public health relevance

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer-related death in the United States. Strong basic research efforts are urgently needed to understand the molecular mechanisms responsible for its aggressiveness and to design novel anti-cancer therapies. Recent studies suggest that, besides their physiological role, mucins play a part in the pathogenesis of cancer: mucin1 (MUC1) overexpression has been observed in various cancers, including pancreatic cancer. It is believed that the carboxy terminal peptide of MUC1 is targeted to the mitochondria and inhibits apoptosis by preventing the release of cytochrome c (Cyt C). However, the mechanism by which MUC1 translocates to the mitochondria is unclear, since MUC1 lacks any mitochondrial localization sequence. It has been suggested that Heat Shock Proteins (HSPs) may participate in the mitochondrial translocation of MUC1, and studies in our laboratory have demonstrated that HSP70 is overexpressed in pancreatic cancer cells, and that the downregulation of HSPs leads to apoptosis. We have also demonstrated that one of the mechanisms by which HSP70 inhibits apoptosis in pancreatic cancer cells is by inhibiting Cyt c release from the mitochondria. However, the mechanism by which HSP70 inhibits Cyt c release from mitochondria remains unclear. We have observed that MUC1 is overexpressed in pancreatic cancer cells, where it also interacts with HSP70. We therefore hypothesize that HSP70 inhibits apoptosis in pancreatic cancer cells by transporting MUC1 to the mitochondria, where MUC1 stabilizes mitochondria, and subsequently prevents Cyt c release. Our preliminary studies indicate that downregulating HSP70 in pancreatic cancer cells leads to lysosomal membrane permeabilization and releases lysosomal enzymes into the cytosol, which then activate the apoptotic cascade. However, the mechanism by which HSP70 stabilizes the lysosomes remains unclear. Our preliminary studies suggest that MUC1 co-localizes to lysosomes. Thus, we hypothesize that HSP70 transports MUC1 to lysosomes, as well, and thereby stabilizes them. This novel hypothesis can explain the mechanism by which both HSP70 and MUC1 inhibit apoptosis in pancreatic cancer cells. The proposed studies have been divided into 4 specific aims: The 1st and 2nd specific aims will evaluate the role of MUC1 in the pathogenesis and aggressiveness of pancreatic cancer and will examine inhibiting MUC1 expression as a potential therapeutic strategy in pancreatic cancer; The 3rd and 4th aims will examine the mechanism by which MUC1 stabilizes lysosomes and mitochondria, and will investigate the role played by HSP70 in such processes. Once completed, these studies will greatly increase our understanding of the mechanisms by which cancer cells evade cell death, and will eventually lead us to design novel treatments. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is the fourth leading cause of cancer-related death in the USA. The severity of this cancer can be appreciated by the fact that in 2006 alone, 33,730 new cases were expected, and almost the same number died of the disease. Thus, efforts to gain information on the pathobiology of pancreatic cancer and on the molecular mechanisms related to the invasion and metastasis of tumor cells are urgently needed in order to develop effective treatments.

描述（由申请人提供）：胰腺癌是美国与癌症有关的第四个主要原因。迫切需要进行强大的基础研究工作，以了解负责其侵略性的分子机制并设计新颖的抗癌疗法。最近的研究表明，除了其生理作用外，粘蛋白在癌症的发病机理中起作用：粘蛋白1（MUC1）过表达在包括胰腺癌在内的各种癌症中。据认为，MUC1的羧基末端肽针对线粒体，并通过防止细胞色素C（Cyt C）释放来抑制凋亡。但是，由于MUC1缺乏任何线粒体定位序列，因此MUC1转移到线粒体的机制尚不清楚。有人提出，热休克蛋白（HSP）可能参与MUC1的线粒体易位，并且在我们的实验室中的研究表明，HSP70在胰腺癌细胞中过表达，并且HSPS的下调导致细胞凋亡。我们还证明，HSP70抑制胰腺癌细胞中凋亡的一种机制之一是抑制线粒体中的Cyt C释放。但是，HSP70抑制从线粒体释放Cyt C的机制尚不清楚。我们已经观察到MUC1在胰腺癌细胞中过表达，在胰腺癌细胞中也与HSP70相互作用。因此，我们假设HSP70通过将MUC1运输到线粒体，在该线粒体上抑制胰腺癌细胞的凋亡，在该线粒体上MUC1稳定线粒体，然后防止Cyt C释放。我们的初步研究表明，胰腺癌细胞中的HSP70下调会导致溶酶体膜通透性化，并释放出溶酶体酶为细胞质，然后激活凋亡的级联反应。但是，HSP70稳定溶酶体的机制尚不清楚。我们的初步研究表明，MUC1共定位于溶酶体。因此，我们假设HSP70也将MUC1传输到溶酶体，从而稳定它们。这个新颖的假设可以解释HSP70和MUC1抑制胰腺癌细胞凋亡的机制。拟议的研究已分为4个特定目的：第一和第二个特定目的将评估MUC1在胰腺癌的发病机理和攻击性中的作用，并将检查抑制MUC1作为胰腺癌中潜在的治疗策略的抑制作用；第三和第四目标将检查MUC1稳定溶酶体和线粒体的机制，并将研究HSP70在此类过程中所起的作用。完成后，这些研究将大大提高我们对癌细胞逃避细胞死亡机制的理解，并最终导致我们设计新的治疗方法。公共卫生相关性：胰腺癌是美国与癌症相关死亡的第四个主要原因。该癌症的严重程度可以通过以下事实来理解：仅在2006年，预计有33,730例新病例，几乎相同的疾病死亡。因此，迫切需要努力获取有关胰腺癌病理生物学以及与肿瘤细胞侵袭和转移有关的分子机制的信息，以开发有效的治疗方法。