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: 7535247
• 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/7535247
• 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; Human; 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 chemoprevention; cancer prevention; cancer therapy; cell growth; high risk; novel strategies; novel therapeutics; oltipraz; prostate cancer prevention; treatment strategy; 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)： 雄激素是强有力的前列腺生长因子，而雄激素耗竭是前列腺癌治疗和/或化学预防的唯一策略。然而，目前前列腺癌的雄激素耗竭策略在降低双氢睾酮(DHT)水平方面只有75%的有效，而前列腺癌的化学预防与显著的副作用和风险相关。因此，我们将测试增强雄激素分解代谢是否可以成为前列腺癌化学预防和/或治疗的一种全新的补充策略，该策略基于以下知识。(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，主要被31-羟基类固醇脱氢酶AKR1C2和32-羟基类固醇脱氢酶AKR1C1分解代谢。(2)我们报道了AKR1C2(和活性较低的AKR1C1)基因在人前列腺癌标本中的表达降低，并与DHT含量增加有关。(3)瞬时或稳定转染所致前列腺癌AKR1C2酶表达增加可抑制DHT依赖基因的表达及随后的细胞增殖。(4)诱导剂还能增加前列腺癌AKR1C2和AKR1C1酶的表达。因此，以下特定目标将测试主要由AKR1C2增强DHT分解代谢是否可以减少DHT依赖的基因表达和肿瘤生长。在特定的目标1中，我们将确定酶AKR1C2(和/或AKR1C1)是否可以调节细胞内DHT水平，从而在培养或裸鼠体内抑制依赖DHT的基因表达和生长。在特定的目标2中，我们将测试AKR1C2(和AKR1C1)的诱导剂是否能够促进~3H-DHT的分解代谢，并在培养或裸鼠体内抑制DHT依赖的基因表达和生长。我们将确认AKR1C2的诱导是这些诱导剂减少DHT依赖效应所必需的。在特定目标3中，将在前列腺特异性条件性磷酸酶和紧张素同源(Pten)纯合子缺失小鼠品系(cPten-/-)中评估诱导剂增强DHT分解代谢的有效性。该诱导剂延缓自发性前列腺癌生长的有效性也将在该小鼠品系中进行评估。因此，这一目的将作为原理的证明，在动物模型中测试增强DHT分解代谢的潜力。总而言之，这三个特定的目标将确立在模型系统中增强DHT分解代谢以减少DHT依赖生长的有效性。如果成功，这些结果将导致未来的建议，以进一步发展这一新的战略，以实现雄激素消耗的化学预防和/或补充治疗前列腺癌。消除前列腺中的雄激素是用于治疗和/或预防前列腺癌的战略。需要新的方法来治疗前列腺癌，因为目前的治疗方法不能完全消除雄激素。我们将测试增强雄激素分解是否可以延缓前列腺癌细胞和小鼠自发性前列腺癌的生长，从而证明这种新方法可以用于前列腺癌的治疗和/或预防。