Glucocorticoid signaling, taxane resistance, and prostate cancer mortality disparity

非裔美国人(AA)男性患上高度侵袭性的前列腺癌，因此死亡的可能性是后者的两倍 比其他种族背景的男性更恶毒。晚期前列腺癌(PCA)通常用以下药物治疗 雄激素剥夺疗法和紫杉烷类药物化疗。不幸的是，死亡一旦发生 癌症会发生转移，并对治疗产生抗药性。最近的研究表明，糖皮质激素受体 (GR)信号使人对紫杉烷化疗产生耐药性；然而，潜在的机制并不是这样 已明确确立或在健康差距的背景下进行研究。糖皮质激素同时存在 用于PCA患者以减轻治疗的副作用，但最近的证据表明，他们 也可能加速疾病的发展。这给AA男性带来了一个严重的问题，他们长期 与欧洲人相比，内源性糖皮质激素水平升高和糖皮质激素信号增强 美国(EA)男性。这些观察结果暗示糖皮质激素信号是前列腺癌的一个潜在因素。 死亡率差异，提示靶向GR可以减轻PCa的治疗耐药性，并减少这些 差距。拟议的研究旨在将升高的GR信号与抗病联系起来 在前列腺癌中进行紫杉烷化疗，并靶向GR逆转这种耐药性。目前，有一个基本的 我们缺乏对GR诱导的化疗耐药在种族背景下的影响的了解 前列腺癌死亡率的差异。这是由该领域的关键障碍造成的，包括缺乏研究。 在健康差异背景下将GR信号与PCA治疗耐药性联系起来，以及对 GR诱导化疗耐药的分子机制。这项提案解决了以下问题 通过探索AA前列腺肿瘤中GR信号增强这一新的总体假设来实现关键障碍 并通过上调应激生存基因来提高化疗耐药性。这一假说得到了 初步数据表明，GR信号强烈诱导耐药基因的表达。 AA来源细胞系中的相关蛋白LEDGF/p75和Clusterin。我们将评估我们的总体假设 通过两个特定的目的：目的1.检验GR直接诱导PCa细胞耐药的假设 通过上调应激生存蛋白。这将在使用AA和EA细胞的机制研究中进行探索 和PCa异种移植模型。目的2.检验患有前列腺癌的AA患者GR信号升高的假设， 导致应激存活蛋白的表达和循环增加。这一点将通过审查 AA和EA患者前列腺癌组织中GR的表达及循环中GR水平的变化 伴有和不伴有前列腺癌的AA和EA患者的LEDGF/p75和Clusterin水平。这些探索性和创新性的研究 用机制方法确定GR信号在促进PCa化疗耐药中的作用 在健康差距的背景下。这些研究的结果将确定治疗的新靶点。 旨在减轻前列腺癌中GR驱动的化疗耐药性，从而减少这些差异。

African American (AA) men develop highly aggressive prostate tumors and are twice as likely to die of this malignancy than men from other racial backgrounds. Advanced prostate cancer (PCa) is usually treated with androgen deprivation therapy and chemotherapy with taxane drugs. Unfortunately, death occurs once the cancer becomes metastatic and resistant to therapy. Recent studies demonstrate that glucocorticoid receptor (GR) signaling confers resistance to taxane chemotherapy; however, the underlying mechanisms have not been clearly established or studied in the context of health disparities. Glucocorticoids are concurrently administered to PCa patients to mitigate the side effects of therapy, but recent evidence suggests that they may also accelerate disease progression. This poses a serious problem for AA men, who have chronically elevated levels of endogenous glucocorticoids and amplified glucocorticoid signaling compared to European American (EA) men. These observations implicate glucocorticoid signaling as a potential contributor to PCa mortality disparities, and suggest that targeting GR may attenuate therapy resistance in PCa and reduce these disparities. The proposed studies are aimed at mechanistically linking elevated GR signaling with resistance to taxane chemotherapy in PCa, and targeting GR to reverse this resistance. Currently, there is a fundamental lack in our understanding of the impact of GR-induced chemotherapy resistance in the context of racial disparities in prostate cancer mortality. This is caused by critical barriers in the field that include lack of studies linking GR signaling to PCa therapy resistance in the context of health disparities, and limited understanding of molecular mechanisms underlying GR-induced chemotherapy resistance. This proposal addresses these critical barriers by exploring the novel overall hypothesis that GR signaling is enhanced in AA prostate tumors and promotes chemotherapy resistance by upregulating stress survival genes. The hypothesis is supported by preliminary data suggesting that GR signaling robustly induces the expression of the chemoresistance- associated proteins LEDGF/p75 and Clusterin in AA-derived cell lines. We will evaluate our overall hypothesis through two specific aims: Aim 1. Test the hypothesis that GR directly induces chemoresistance in PCa cells by upregulating stress survival proteins. This will be explored in mechanistic studies using AA and EA cellular and xenograft models of PCa. Aim 2. Test the hypothesis that GR signaling is elevated in AA men with PCa, leading to increased expression and circulation of stress survival proteins. This will be explored by examining the expression of GR in prostate tumor tissues from AA and EA patients, as well as the circulating levels of LEDGF/p75 and Clusterin in AA and EA men with and without PCa. These exploratory and innovative studies use a mechanistic approach to establish the role of GR signaling in promoting chemotherapy resistance in PCa in the context of health disparities. The results from these studies will identify new targets for therapies designed to attenuate GR driven chemoresistance in PCa, resulting in reduction of these disparities.