臭椿酮靶向Trx1调控CRPC细胞内ROS平衡逆转ADT耐受的分子机制研究

Prostate cancer (PrCa) is the most commonly diagnosed cancer among men in Western industrialized nations. Advanced PrCa is treated with androgen deprivation therapy (ADT), and although there is usually a significant initial response, recurrence arises as castration-resistant prostate cancer (CRPC). New approaches are needed to treat this genetically heterogeneous, phenotypically plastic disease. CRPC with androgen receptor (AR) overexpression is specifically featured with evaluated intracellular reactive oxygen species (ROS). Meanwhile, thioredoxin (Trx), which is the key node of the intracellular anti-oxidative system, is reported to be elevated in CRPC comparing to early stage PrCa. Clinical comparative analysis of Trx expression indicates it is progressively and significantly elevated in going from normal prostate tissue samples to AD-responsive PrCa samples to metastatic CRPC samples with high Gleason score，indicating an emerging treatment strategy to anchor Trx in CRPC. Ailanthone (AIL) is a naturally occurring polyprenylated xanthonebased moiety. Our Previous results have identified it as a highly potent growth inhibitor and overcame ADT resistace in CRPC with the mechanism not fully revealed. With the advance of organiods culture of various tumors from the genomically representative LuCaP metastic CRPC patient-derived xenograft(PDX) cohort, our study is designed to establish a new compound inhibiting Trx and reversing the sensitivity of CRPC to ADT in diverse clinical relevant models to set an new angle as for the therapeutic strategy of CRPC.

前列腺癌是西方国家男性中最常见的恶性肿瘤之一，雄激素去势治疗后进展的激素抵抗性前列腺癌是治疗难点。大量研究显示作为一种临床异质性极高的肿瘤，激素抵抗性前列腺癌组织内同时存在过表达的雄激素受体和异常聚集的活性氧类。硫氧还蛋白（Thioredoxin，Trx），作为细胞内活性氧类清除系统的主要成员，在激素抵抗性前列腺癌中过表达，临床研究也提示其表达水平与Gleason评分正相关。前述研究结果均提示以Trx为治疗靶点在转移性前列腺癌的治疗中具有广泛的研究和应用前景。臭椿酮作为一种天然的氧杂蒽环类衍生物，前期研究显示具有较强的抗激素抵抗性前列腺癌活性，提高雄激素疗法的敏感性，具体机制有待全面揭示。本研究旨在以来源于不同遗传背景的初代人源性激素抵抗性前列腺癌细胞的三维培养细胞球为研究对象，全面揭示臭椿酮靶向Trx抑制激素抵抗性前列腺癌细胞生长、逆转雄激素去势疗法耐药的机制，为激素抵抗性前列腺的治疗提供新的策略。

前列腺癌发病率据男性恶性肿瘤第一，其中雄激素去势治疗后进展的激素抵抗性前列腺癌是治疗难点，总体疗效不佳，迫切需要探索寻找新的治疗策略及靶点。本研究证实臭椿酮作为一种天然的氧杂蒽环类衍生物，纳摩尔浓度即可抑制来源于不同遗传背景的初代人源性激素抵抗性前列腺癌细胞的三维培养细胞球，具有较强的抗激素抵抗性前列腺癌活性，提高了激素抵抗性前列腺癌细胞对恩杂鲁胺的敏感性。进一步机制研究提示臭椿酮可以通过下调细胞内Trx1水平影响ROS、抑制STAT3的磷酸化从而抑制myc表达，引起激素抵抗性前列腺癌细胞的凋亡和周期阻滞。本研究为激素抵抗性前列腺的治疗提供新的策略。