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Death receptors in prostate cancer biology and apoptosis

前列腺癌生物学和细胞凋亡中的死亡受体

基本信息

批准号：
6514803
负责人：
M. SAEED SHEIKH
金额：
$ 15.2万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-07-01 至 2004-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6514803
关键词：
apoptosis biological signal transduction complementary DNA cytokine receptors ionizing radiation microarray technology neoplasm /cancer pharmacology nonsteroidal antiinflammatory agent northern blottings nuclear factor kappa beta prostate neoplasms radiation sensitivity tumor necrosis factor alpha western blottings

项目摘要

DESCRIPTION (provided by applicant): The main goals of this proposal is to explore the role of membrane death receptors and their ligands in nonsteroidal anti-inflammatory drugs (NSAIDs) and ionizing radiation (IR)-induced apoptosis in human prostate cancer cells. Evidence suggests that the regular use of NSAIDs reduces the risk of other cancer types but their role in prevention of prostate cancer has not been elucidated. NSAIDs are believed to mediate their chemopreventive and anti-tumorigenic effects by inducing apoptosis. IR is an important therapeutic modality against prostate cancer and is believed to kill prostate cancer cells by inducing apoptosis. However, the biochemical and molecular pathways via which these agents induce apoptosis have not been fully elucidated. Preliminary results presented in this proposal indicate that sulindac sulfide, a clinically relevant NSAID, induces apoptosis in human prostate cancer cells. Sulindac sulfide also augments ionizing radiation (IR)-induced apoptosis in human prostate cancer cells. Preliminary evidence presented in this application further suggests that death receptor 5 (DR5) may be involved in transducing the apoptotic signals of sulindac sulfide and IR. Thus, the role of DR5 and its ligand in this context will be explored. Similarly, the contribution of other death receptors and their ligands in sulindac sulfide, IR and sulindac sulfide+IR-mediated apoptosis will be investigated. DR5 activation stimulates apoptotic pathway and NF-kB-dependent survival pathway. IR activates NF-kB while sulindac is known to inhibit NF-kB. Thus, the role of NF-kB in sulindac sulfide-induced radiosensitization will also be explored. The long-term objectives of this proposal are to (i) better understand the apoptotic signaling pathways in human prostate cancer cells and (ii) lay the ground work to potentially develop a novel treatment and/or prevention strategy against this deadly disease.

描述(由申请人提供)：本提案的主要目标是膜死亡受体及其配体在非甾体激素中的作用抗炎药和电离辐射诱导的细胞凋亡在人类前列腺癌细胞中。有证据表明，经常使用非类固醇抗炎药可降低患其他癌症的风险，但它们在预防癌症方面的作用前列腺癌还没有被阐明。非甾体抗炎药被认为可以调节他们的通过诱导细胞凋亡发挥化学预防和抗肿瘤作用。IR是一种前列腺癌的重要治疗方法，据信可以杀死通过诱导前列腺癌细胞的凋亡。然而，生化和这些药物诱导细胞凋亡的分子途径还不完全清楚。已澄清。该提案中提出的初步结果表明，舒林酸硫化物，一种临床相关的非甾体抗炎药，诱导人类细胞凋亡前列腺癌细胞。硫化舒林酸也会增加电离辐射。 (IR)诱导人前列腺癌细胞的凋亡。初步证据在本申请中提出的进一步表明死亡受体5(DR5)可以参与硫化舒林酸和IR细胞凋亡信号的转导。因此，我们将探讨DR5及其配体在这方面的作用。同样，其他死亡受体及其配体在体内的作用硫化舒林酸、IR及硫化舒林酸+IR介导的细胞凋亡调查过了。DR5激活刺激细胞凋亡途径和核因子-kB依赖生存之路。IR激活了核因子-kB，而舒林酸则抑制了核因子-kB。因此，核因子-kB在硫化硫诱导的放射增敏中的作用将也是被探索的。这项建议的长期目标是：(I)更好地了解人前列腺癌细胞中的凋亡信号通路和 (Ii)为可能开发新的治疗方法和/或预防这一致命疾病的战略。