Bid-mediated killing of oncogenic stem cells in chemoprevention

* 描述(由申请人提供)：使用非类固醇抗炎药(NSAIDs)等药物进行结直肠癌的化学预防已成为降低该疾病发病率和死亡率的一种有希望的策略。然而，非甾体类抗炎药和其他化学预防药物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，非类固醇抗炎药通过BID(一种促凋亡的Bcl-2家族蛋白)触发外源性和内在凋亡途径之间的串扰，从而杀死结肠癌细胞。缺乏BID几乎完全取消了非甾体抗炎药舒林酸对APC/Min小鼠的化学预防作用，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信号的肠道干细胞的凋亡。来自服用非类固醇抗炎药的患者的腺瘤样本也被发现增强了具有干细胞特征和Wnt信号异常的细胞的凋亡诱导。因此，我们假设非甾体抗炎药通过BID介导的细胞凋亡清除致癌的肠道干细胞，从而抑制肠道肿瘤的形成。为了验证这一假说，我们将研究：1)NSAIDs特异性激活BID杀伤肿瘤细胞的机制；2)NSAI诱导和BID介导的细胞凋亡选择性杀伤肿瘤干细胞；3)BID介导的致癌干细胞凋亡在NSAIDs对小鼠的化学预防中的作用；4)NSAIDs在腺瘤患者化学预防中对肿瘤干细胞的杀伤作用。这些研究将描绘NSAIDs在结直肠癌化学预防中的关键活性和分子靶点，并深入了解为什么NSAID化学预防对某些患者有益，但不是所有患者。这些研究结果可能为未来开发具有更高疗效和特异性的化学预防药物提供可能性，并可能有助于合理设计更有效的策略来改善结直肠癌化学预防的结果。

* 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.