Targeting DHT Catabolism by AKR1Cs for Prostrate Cancer Prevention and Treatment.

通过 AKR1C 靶向 DHT 分解代谢来预防和治疗前列腺癌。

• 批准号: 7372377
• 负责人: ANDREW Abba STOLZ
• 金额: $ 30.44万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-03 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7372377
• 关键词: 3-Hydroxysteroid Dehydrogenases; AKR1C1; Adverse effects; Androgen Receptor; Androgens; Animal Model; Binding; Biological Models; Cancer cell line; Catabolism; Cell Line; Cell Proliferation; Cells; Chemoprevention; Chemopreventive Agent; Complement; Decreased Libido; Effectiveness; Ensure; Enzymes; Epithelial Cells; Ethacrynic Acid; Future; Gene Expression; Genes; Growth; Growth Factor; Hydroxysteroid Dehydrogenases; Incidence; Knowledge; Lead; Ligands; Malignant neoplasm of prostate; Messenger RNA; Mouse Strains; Mus; Nude Mice; PC3 cell line; PTEN gene; Phase; Prevention; Prostate; Prostatic; Prostatic Neoplasms; Regulation; Reporter; Reporting; Risk; Sampling; Serum; Stanolone; Testing; Testosterone; Transfection; Xenograft procedure; base; cancer cell; cancer prevention; cancer therapy; cell growth; novel strategies; novel therapeutics; oltipraz; prostate cancer prevention; tumor; tumor growth

DESCRIPTION (provided by applicant): Androgens are potent prostatic growth factors, and androgen-depletion is the sole strategy for the treatment and/or chemoprevention of prostate cancer. However, current androgen-depletion strategies for prostate cancer are only 75% effective at reducing dihydrotestosterone (DHT) levels and for prostate cancer chemoprevention are associated with significant side effects and risk. Consequently, we will test whether enhanced androgen catabolism can be an entirely new and complementary strategy for both the chemoprevention and/or treatment of prostate cancer, a strategy based on the following knowledge. (1) In the prostate, the androgen DHT, which activates the androgen receptor, is intracellularly synthesized from serum testosterone and catabolized primarily by AKR1C2 a 31-hydroxysteroid dehydrogenase and AKR1C1 a 32- hydroxysteroid dehydrogenase. (2) We reported that AKR1C2 (and the less active AKR1C1) gene expression in human prostate tumor samples is reduced and is associated with increased DHT content. (3) Increased AKR1C2 enzyme expression in prostate cancer cell lines due to transient or stable transfection can diminish DHT-dependent gene expression and subsequent cellular proliferation. (4) Inducers can also increase AKR1C2 and AKR1C1 enzyme expression in prostate cancer cell lines. Thus, the following Specific aims will test whether enhancing DHT catabolism, predominately by AKR1C2, can diminish DHT-dependent gene expression and tumor growth. In Specific Aim 1, we will determine whether enzyme AKR1C2 (and/or AKR1C1) can regulate intracellular DHT level and subsequently diminish DHT-dependent gene expression and growth of prostrate cancer cell line in culture or in athymic nude mice. In Specific Aim 2, we will test whether inducers of AKR1C2 (and AKR1C1) can enhance 3H-DHT catabolism, and diminish DHT-dependent gene expression and growth of prostate cancer cell lines in culture or in athymic mice. We will confirm that induction of AKR1C2 is required for diminution of DHT-dependent effects by these inducers. In Specific Aim 3, the effectiveness of enhanced DHT-catabolism by inducers will be evaluated in cell lines derived from spontaneous prostate tumors in a prostate specific conditional phosphatase and tensin homolog (Pten) homozygous deleted mouse strain (cPten-/-). The effectiveness of the inducer to delay the growth of spontaneous prostate tumors will also be evaluated in this mouse strain. Thus, this aim will test as a proof of principle the potential of enhancing DHT catabolism in an animal model. In summary, these three Specific Aims will establish the effectiveness of enhancing DHT catabolism to diminish DHT-dependent growth in model systems. If successful, these results will lead to future proposals to further develop this new strategy for achieving androgen-depletion for both the chemoprevention and/or to complement treatment of prostate cancer.Eliminating androgens in the prostate is the strategy used for the treatment and/or prevention of prostate cancer. New approaches are needed to treat prostate cancer because current treatments incompletely eliminate androgens. We will test whether enhancing androgen break down can delay the growth of prostate cancer cells and of spontaneous prostate tumors in a mouse strain, and thus prove that this new approach can be used for prostate cancer treatment and/or prevention.

描述（由申请人提供）： 雄激素是有效的前列腺生长因子，雄激素耗竭是治疗和/或化学预防前列腺癌的唯一策略。然而，目前用于前列腺癌的雄激素耗竭策略在降低双氢睾酮（DHT）水平方面仅75%有效，并且用于前列腺癌化学预防与显著的副作用和风险相关。因此，我们将测试增强的雄激素catalysts是否可以是一个全新的和互补的策略，用于前列腺癌的化学预防和/或治疗，一个基于以下知识的策略。(1)在前列腺中，激活雄激素受体的雄激素DHT由血清睾酮在细胞内合成，并主要由AKR 1C 2（31-羟基类固醇脱氢酶）和AKR 1C 1（32-羟基类固醇脱氢酶）分解代谢。(2)我们报道了AKR 1C 2（和活性较低的AKR 1C 1）基因在人前列腺肿瘤样本中的表达减少，并与DHT含量增加有关。(3)由于瞬时或稳定转染导致的前列腺癌细胞系中AKR 1C 2酶表达增加可以减少DHT依赖性基因表达和随后的细胞增殖。(4)诱导剂还可以增加前列腺癌细胞系中AKR 1C 2和AKR 1C 1酶的表达。因此，以下具体目标将测试主要通过AKR 1C 2增强DHT催化剂是否可以减少DHT依赖性基因表达和肿瘤生长。在具体目标1中，我们将确定酶AKR 1C 2（和/或AKR 1C 1）是否可以调节细胞内DHT水平，并随后减少培养物或无胸腺裸鼠中前列腺癌细胞系的DHT依赖性基因表达和生长。在特定目标2中，我们将测试AKR 1C 2（和AKR 1C 1）的诱导剂是否可以增强3 H-DHT催化剂，并减少培养或无胸腺小鼠中前列腺癌细胞系的DHT依赖性基因表达和生长。我们将证实，诱导AKR 1C 2是减少这些诱导剂的DHT依赖性作用所必需的。在特定目标3中，将在源自前列腺特异性条件性磷酸酶和张力蛋白同源物（Pten）纯合缺失小鼠品系（cPten-/-）的自发性前列腺肿瘤的细胞系中评价诱导剂增强的DHT-催化剂的有效性。还将在该小鼠品系中评价诱导剂延迟自发性前列腺肿瘤生长的有效性。因此，该目的将测试作为在动物模型中增强DHT催化剂的潜力的原理证明。总之，这三个具体目标将确定增强DHT催化剂的有效性，以减少模型系统中依赖DHT的生长。如果成功的话，这些结果将导致未来的建议，以进一步发展这种新的策略，实现雄激素耗竭的化学预防和/或补充治疗前列腺癌。消除雄激素在前列腺是用于治疗和/或预防前列腺癌的策略。需要新的方法来治疗前列腺癌，因为目前的治疗不完全消除雄激素。我们将测试增强雄激素分解是否可以延迟小鼠品系中前列腺癌细胞和自发性前列腺肿瘤的生长，从而证明这种新方法可用于前列腺癌的治疗和/或预防。