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: 7738944
• 负责人: ANDREW Abba STOLZ
• 金额: $ 30.35万
• 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/7738944
• 关键词: AKR1C1; Adverse effects; Affect; Androgen Receptor; Androgens; Animal Model; Animals; Antioxidants; Biological Models; Cancer cell line; Castration; Catabolism; Cell Line; Cell Proliferation; Cells; Chemoprevention; Complement; Data; Diet; Dose; Effectiveness; Ensure; Enzymes; Experimental Designs; Future; Gene Expression; Genes; Growth; Growth Factor; Human; Hydroxysteroid Dehydrogenases; Immunohistochemistry; Implant; Incubated; Intestines; Kinetics; Knowledge; Label; Lead; Liver; Malignant neoplasm of prostate; Methodology; Methods; Mouse Strains; Mus; Nude Mice; Outcome; PC3 cell line; PTEN gene; Parents; Pathway interactions; Phase; Prevention; Prostate; Prostatic; Prostatic Neoplasms; Protocols documentation; Rattus; Relative (related person); Reporter; Reporting; Risk; Ru-1881; Sampling; Serum; Stanolone; Sterilization; Subfamily lentivirinae; Testing; Testosterone; Transfection; Xenograft procedure; base; cancer cell; cancer chemoprevention; cancer prevention; cancer therapy; chemical stability; cytotoxicity; feeding; human MPP1 protein; irradiation; mutant; novel strategies; oltipraz; prevent; prostate cancer prevention; protein expression; research study; treatment strategy; tumor; tumor growth; tumor progression

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，雄激素消耗是治疗和/或化学预防前列腺癌的唯一策略。但是，目前针对前列腺癌的雄激素止血策略仅在降低二氢睾丸激素（DHT）水平和前列腺癌化学预防的有效效果上有效，这与显着的副作用和风险有关。因此，我们将测试增强的雄激素分解代谢是否可以成为化学预防和/或治疗前列腺癌的全新且互补的策略，这是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是从血清睾丸激素中合成的，主要由AKR1C2 A AKR1C2 A 31-羟基类脱氢酶和AKR1C1 AKR1C1 AKR1C1 A 32-羟基羟基生产酶进行分解。 （2）我们报道说，人类前列腺肿瘤样品中的AKR1C2（和较不活跃的AKR1C1）基因表达减少，并且与DHT含量增加有关。 （3）由于短暂或稳定转染而增加了前列腺癌细胞系中AKR1C2酶的表达会减少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的AKR1C2和AKR1C1酶的表达。因此，以下特定目的将测试以AKR1C2为主的增强DHT分解代谢是否可以减少DHT依赖性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，然后降低培养物或丘脑裸鼠中pros癌细胞系的DHT依赖性基因表达和生长。在特定的目标2中，我们将测试AKR1C2（和AKR1C1）的诱导剂是否可以增强3H-DHT分解代谢，并降低DHT依赖性基因表达和前列腺癌细胞系在培养物中或在胸腺小鼠中的生长。我们将确认这些诱导剂减少DHT依赖性效应所必需的AKR1C2诱导。在特定的目标3中，将在前列腺特异性磷酸酶和Tensin同源性（PTEN）纯合菌株菌株（CPTEN-/ - ）中评估诱导剂增强的DHT-Catebolism的有效性。诱导剂延迟自发前列腺肿瘤生长的有效性也将在该小鼠菌株中评估。因此，该目标将作为原理证明，增强动物模型中DHT分解代谢的潜力。总而言之，这三个具体目标将确定增强DHT分解代谢以减少模型系统中DHT依赖性增长的有效性。如果成功，这些结果将导致未来的提案，以进一步制定这种新的策略，以实现化学预防和/或补充前列腺癌的治疗方法。将前列腺中的雄激素用于治疗和/或预防前列腺癌。需要新的方法来治疗前列腺癌，因为目前的治疗方法不完全消除了雄激素。我们将测试增强雄激素分解是否可以延迟小鼠菌株中前列腺癌细胞和自发前列腺肿瘤的生长，从而证明这种新方法可用于前列腺癌治疗和/或预防。