Piperlongumine: A Novel Inhibitor of Androgen Receptor Signaling

Piperlongumine：雄激素受体信号传导的新型抑制剂

• 批准号: 8302819
• 负责人: VLADIMIR M KOLENKO
• 金额: $ 8.93万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-09 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8302819
• 关键词: Ablation; Accounting; Affect; Androgen Antagonists; Androgen Receptor; Androgens; Black Pepper; Cell Proliferation; Cessation of life; Clinical Research; Diagnosis; Disease; Disease Progression; Exhibits; Failure; Growth; Heat-Shock Proteins 90; Hormonal; Hormones; Human; Indolent; LNCaP; Malignant neoplasm of prostate; Mediating; Molecular; Molecular Chaperones; PTEN gene; Pathway interactions; Patients; Phenotype; Play; Prostate; Prostatic Tissue; Receptor Activation; Receptor Signaling; Regimen; Role; Staging; Systemic Therapy; Testing; Therapeutic; Time; Transgenic Mice; Variant; Work; Xenograft Model; abiraterone; advanced disease; cancer cell; cancer initiation; cancer risk; deprivation; hormone therapy; in vivo; in vivo Model; inhibitor/antagonist; mouse model; multicatalytic endopeptidase complex; novel; overexpression; prostate cancer prevention; prostate carcinogenesis; protein protein interaction; receptor; receptor expression; research study; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The burden of prostate cancer (PC) is tremendous, accounting for approximately 220,000 new cases and 32,050 deaths in the US in 2010 alone. In many patients, PC exhibits an indolent biologic phenotype with a prolonged course-in some cases, extending over 15 years following the initial diagnosis. Thus, the opportunity to intervene early and alter the course and progression of this disease is readily available. Androgen receptor (AR) signaling plays a crucial role in the normal growth of the prostate as well as in PC initiation and progression. Thus, modulation of AR activation and expression represents a logical target for PC prevention and treatment. Recent clinical studies demonstrate that pharmacological inhibition of AR signaling reduces PC risk. However, AR- mediated functions are not completely abrogated by existing hormone therapies. Therapeutic failure is often accompanied by molecular alterations of the AR, including AR overexpression as well as expression of constitutively active AR variants. Our experiments demonstrate for the first time that piperlongumine (PL), a naturally occurring derivative of black pepper, induces rapid AR degradation through a proteasome-mediated pathway which coincides with inhibition of AR transcriptional activity and reduced proliferation of hormone- dependent LNCaP PC cells. We hypothesize that PL can inhibit prostate carcinogenesis at both initiation and advanced disease stages via depletion of the AR either alone or in combination with current androgen deprivation therapeutic regimens. Indeed, hormone ablation and depletion of AR may have a complementary effect on the inhibition of prostate carcinogenesis. The overall objective of this application is to explore the mechanisms of PL- mediated AR depletion and to test PL efficacy for the primary and secondary PC prevention. To test our hypothesis and to evaluate the therapeutic potential of PL for prostate cancer prevention, we propose the following Specific Aims: Aim 1: To investigate the mechanism of PL-mediated AR depletion in prostate cancer cells. Specific Aim 2: To investigate the effect of PL on primary and secondary PC prevention using in vivo models. PUBLIC HEALTH RELEVANCE: Androgen receptor signaling plays a crucial role in the normal growth of prostatic tissue as well as in prostate cancer initiation and progression. Our work demonstrates for the first time that piperlongumine, a naturally occurring derivative of black pepper, induces rapid androgen receptor degradation in prostate cancer cells through a proteasome-mediated pathway which coincides with reduced functional activity of androgen receptor signaling and decreased cell proliferation. The overall objective of this application is t explore the mechanisms of piperlongumine-mediated androgen receptor depletion and to test piperlongumine efficacy for the primary and secondary prostate cancer prevention.

描述（由申请人提供）：前列腺癌（PC）的负担是巨大的，仅在2010年美国就有大约220，000例新发病例和32，050例死亡。在许多患者中，PC表现出惰性生物表型，病程延长，在某些情况下，在最初诊断后延长15年以上。因此，早期干预和改变这种疾病的病程和进展的机会是现成的。雄激素受体（AR）信号转导在前列腺的正常生长以及PC的发生和发展中起着至关重要的作用。因此，AR激活和表达的调节代表了PC预防和治疗的逻辑目标。最近的临床研究表明，AR信号的药理学抑制可降低PC风险。然而，AR介导的功能不能被现有的激素疗法完全消除。治疗失败通常伴随着AR的分子改变，包括AR过表达以及组成型活性AR变体的表达。我们的实验第一次证明了胡椒碱（PL），一种天然存在的黑胡椒衍生物，通过蛋白酶体介导的途径诱导快速AR降解，这与AR转录活性的抑制和激素依赖性LNCaP PC细胞增殖的减少一致。我们假设PL可以通过单独或与目前的雄激素剥夺治疗方案相结合的AR耗竭来抑制前列腺癌的发生。事实上，激素消融和AR耗竭可能对抑制前列腺癌发生具有互补作用。本申请的总体目标是探索PL介导的AR耗竭的机制，并测试PL对一级和二级PC预防的功效。为了验证我们的假设并评估PL预防前列腺癌的治疗潜力，我们提出以下具体目的：目的1：研究前列腺癌细胞中PL介导的AR耗竭的机制。具体目标2：使用体内模型研究PL对一级和二级PC预防的影响。 公共卫生关系：雄激素受体信号传导在前列腺组织的正常生长以及前列腺癌的发生和发展中起着至关重要的作用。我们的工作首次证明，胡椒碱，黑胡椒的天然衍生物，诱导前列腺癌细胞中的雄激素受体的快速降解，通过蛋白酶体介导的途径，这与雄激素受体信号传导的功能活性降低和细胞增殖减少相一致。本申请的总体目的是探索piperlongumine介导的雄激素受体耗竭的机制，并测试piperlongumine对前列腺癌的一级和二级预防效果。