Death receptors in prostate cancer biology and apoptosis

描述（由申请人提供）：本提案的主要目标是 探索膜死亡受体及其配体在非甾体激素 抗炎药（NSAID）和电离辐射（IR）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 NSAIDs降低了其他癌症类型的风险，但它们在预防 前列腺癌尚未阐明。NSAID被认为是介导其 通过诱导细胞凋亡的化学预防和抗肿瘤作用。IR是一个 前列腺癌是一种重要的治疗方式， 前列腺癌细胞凋亡。然而，生物化学和 这些药物诱导细胞凋亡的分子途径还没有完全 阐明。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NSAID，诱导人细胞凋亡 前列腺癌细胞舒林酸硫化物也增加电离辐射 （IR）诱导的人前列腺癌细胞凋亡。初步证据 在本申请中提出的死亡受体5（DR 5）进一步表明，死亡受体5（DR 5）可能 参与舒林酸硫化物和IR的凋亡信号转导。 因此，DR 5及其配体在这种情况下的作用将被探索。 类似地，其他死亡受体及其配体在 舒林酸硫化物，IR和舒林酸硫化物+IR介导的细胞凋亡将是 研究了DR 5激活刺激凋亡途径和NF-kB依赖性 生存之路IR激活NF-κ B，而舒林酸已知抑制NF-κ B。 因此，NF-kB在舒林酸硫化物诱导的放射增敏中的作用将 也可以探索。这项建议的长远目标是：（i）改善 了解人类前列腺癌细胞中的凋亡信号通路， (ii)奠定基础工作，以潜在地开发新的治疗和/或 针对这种致命疾病的预防策略。

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.