Piperlongumine: A Novel Inhibitor of Androgen Receptor Signaling

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22万新病例和32,050例死亡。在许多患者中，PC表现为惰性生物表型，病程延长-在某些情况下，在最初诊断后延长超过15年。因此，早期干预和改变这种疾病的过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发生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的一个逻辑目标。最近的临床研究表明，药物抑制AR信号可降低PC风险。然而，AR介导的功能并没有被现有的激素疗法完全废除。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。我们的实验首次证明，胡椒明（PL）是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AR快速降解，这与抑制AR转录活性和减少激素依赖性LNCaP PC细胞的增殖相一致。我们假设，通过单独或联合目前的雄激素剥夺治疗方案，PL可以在疾病初期和晚期抑制前列腺癌的发生。事实上，激素消融和AR的消耗可能在抑制前列腺癌发生方面具有互补作用。本应用程序的总体目标是探索PL介导的AR耗竭机制，并测试PL在一级和二级PC预防中的功效。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PL介导的前列腺癌细胞中AR耗竭的机制。具体目的2：通过体内模型研究PL对原发性和继发性PC的预防作用。

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.