Bid-mediated killing of oncogenic stem cells in chemoprevention

化学预防中 Bid 介导的致癌干细胞杀伤

• 批准号: 9026577
• 负责人: Lin Zhang
• 金额: $ 31.96万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9026577
• 关键词: Adjuvant Therapy; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Apoptotic; BCL2 gene; Bax protein; Biochemical; Biological; Cancer Etiology; Carcinogens; Cell Death; Cells; Cessation of life; Characteristics; Chemical Agents; Chemoprevention; Chemopreventive Agent; Chronic; Clinical; Colon Carcinoma; Colorectal Cancer; Development; Disease; Epithelial; Epithelial Cells; Future; General Population; Genetic; Health; Induction of Apoptosis; Intestinal Neoplasms; Intestines; Malignant Neoplasms; Mediating; Mitochondria; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mus; Oncogenic; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Protein Family; Proteins; Receptor Signaling; Research Design; Resistance; Role; Sampling; Signal Transduction; Specificity; Stem cells; Structure; Sulindac; Testing; Therapeutic; United States; adenoma; base; cancer cell; cancer chemoprevention; cancer prevention; cancer risk; cancer therapy; cancer type; cell type; clinically relevant; design; dietary manipulation; genetic analysis; improved; improved outcome; insight; killings; mortality; neoplastic; neoplastic cell; prevent; response; tumor

* DESCRIPTION (provided by applicant): Chemoprevention of colorectal cancer using agents such as non-steroidal anti- inflammatory drugs (NSAIDs) has emerged as a promising strategy to reduce the morbidity and mortality of this disease. However, the anti-neoplastic mechanisms of NSAIDs and other chemopreventive agents remain unclear. We have been investigating the mechanisms of NSAID-mediated chemoprevention with the long-term objective of developing improved strategies for reducing cancer risk. Our recent preliminary studies demonstrate that NSAIDs kill colon cancer cells by triggering a crosstalk between the extrinsic and intrinsic apoptotic pathways through Bid, a proapoptotic Bcl-2 family protein. Deficiency in Bid almost completely abolished the chemopreventive effect of the NSAID sulindac in APC/Min mice, a commonly used chemoprevention model. NSAID treatment preferentially induced apoptosis in intestinal stem cells with oncogenic Wnt signaling. Adenoma samples from patients taking NSAIDs were also found to have enhanced apoptosis induction in cells with stem cell characteristics and aberrant Wnt signaling. We therefore hypothesize that NSAIDs inhibit intestinal tumor formation by eliminating oncogenic intestinal stem cells through Bid-mediated apoptosis. To test this hypothesis, we will investigate: 1) the mechanism by which NSAIDs specifically activate Bid to kill tumor cells; 2) selective killing of oncogenic stem cells by NSAI-induced and Bid-mediated apoptosis; 3) role of Bid-mediated oncogenic stem cell apoptosis in chemoprevention by NSAIDs in mice; 4) killing of oncogenic stem cells by NSAIDs in chemoprevention of adenoma patients. These studies will delineate the critical activity and molecular targets of NSAIDs in chemoprevention of colorectal cancer, and shed insight on why NSAID chemoprevention is beneficial for some, but not all patients. The results of these studies may open up the possibility for future development of chemopreventive agents with improved efficacy and specificity, and could be useful for rational design of more effective strategies to improve outcomes of chemoprevention of colorectal cancer.

* 描述（由申请人提供）：使用诸如非甾体抗炎药（NSAID）的药物进行结肠直肠癌的化学预防已经成为降低这种疾病的发病率和死亡率的有前景的策略。然而，NSAID和其他化学预防剂的抗肿瘤机制仍不清楚。我们一直在研究NSAID介导的化学预防的机制，长期目标是开发降低癌症风险的改进策略。我们最近的初步研究表明，NSAID通过Bid（一种促凋亡Bcl-2家族蛋白）触发外源性和内源性凋亡途径之间的串扰来杀死结肠癌细胞。Bid缺乏几乎完全消除了NSAID舒林酸在APC/Min小鼠中的化学预防作用，这是一种常用的化学预防模型。NSAID治疗优先诱导具有致癌Wnt信号传导的肠干细胞凋亡。来自服用NSAID的患者的腺瘤样品也被发现在具有干细胞特征和异常Wnt信号传导的细胞中具有增强的凋亡诱导。因此，我们假设NSAID通过BID介导的凋亡消除致癌肠干细胞来抑制肠肿瘤形成。为了验证这一假设，我们将研究：1）NSAID特异性激活Bid杀死肿瘤细胞的机制; 2）通过NSAID诱导和Bid介导的细胞凋亡选择性杀死致癌干细胞; 3）Bid介导的致癌干细胞凋亡在NSAID化学预防中的作用; 4）NSAID在腺瘤患者化学预防中杀死致癌干细胞。这些研究将描述NSAID在结直肠癌化学预防中的重要活性和分子靶点，并深入了解NSAID化学预防对某些患者有益的原因，但不是所有患者。这些研究的结果可能为未来开发具有更高疗效和特异性的化学预防剂开辟了可能性，并可能有助于合理设计更有效的策略来改善结直肠癌的化学预防结果。