Piperlongumine: A Novel Inhibitor of Androgen Receptor Signaling

描述(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例新病例和32,050例死亡。在许多患者中，PC表现出一种惰性的生物学表型，病程较长--在某些情况下，在最初诊断后持续15年以上。因此，早期干预和改变这种疾病的进程和进展的机会是现成的。雄激素受体(AR)信号在前列腺的正常生长以及前列腺癌的启动和发展中起着至关重要的作用。因此，调节AR的激活和表达是预防和治疗PC的合理靶点。最近的临床研究表明，对AR信号的药物抑制可以降低PC的风险。然而，AR介导的功能并没有被现有的激素疗法完全取消。治疗失败通常伴随着AR的分子改变，包括AR的过度表达以及结构性活性AR变异体的表达。我们的实验首次证明，胡椒素(PL)是一种天然存在的黑胡椒衍生物，它通过蛋白酶体介导的途径诱导AR快速降解，这与抑制AR转录活性和减少激素依赖的LNCaP PC细胞的增殖一致。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联合使用AR来抑制疾病初期和晚期前列腺癌的发生。事实上，激素消融和AR的耗尽可能在抑制前列腺癌发生方面具有互补作用。这项应用的总体目标是探索PL介导的AR耗竭的机制，并测试PL对初级和二级PC预防的有效性。为了验证我们的假设并评估PL预防前列腺癌的治疗潜力，我们提出了以下具体目标：目的1：研究PL介导的前列腺癌细胞AR耗竭的机制。具体目的2：利用体内模型研究PL对初级和二级前列腺癌预防的影响。 公共卫生相关性：雄激素受体信号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，黑胡椒的天然衍生物胡椒胺通过蛋白酶体介导的途径诱导前列腺癌细胞雄激素受体的快速降解，这与雄激素受体信号转导功能活性降低和细胞增殖减少相吻合。该应用的总体目标是探讨胡萝卜素介导的雄激素受体耗竭的机制，并测试胡萝卜素预防前列腺癌的效果。

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.