HORMONAL REGULATION OF PROSTATE CITRATE PRODUCTION

前列腺癌是男性癌症死亡的第二大原因，与良性前列腺增生（BPH）一起，是男性主要的肿瘤疾病。在人类中，前列腺具有独特的功能，可以产生和分泌非常高水平的柠檬酸盐。前列腺的这些生理功能是由睾酮和催乳素调节的。丧失生产柠檬酸的能力是前列腺癌的一个特征，也是与前列腺恶性肿瘤发展相关的首批代谢变化之一。另一方面，腺性前列腺增生的特点是产生分泌性上皮细胞的柠檬酸盐过度增殖，从而产生比正常腺体更高的柠檬酸水平。直接参与前列腺上皮细胞合成柠檬酸盐的两个关键酶是线粒体天冬氨酸转氨酶（mAAT）和丙酮酸脱氢酶（PDH）。这两种酶都受睾丸激素和催乳素的调节。这项拨款申请的主要目的是阐明催乳素调节这些中间代谢酶的表达和活性的机制；阐明所涉及的细胞内信号通路，并利用这些信息开发前列腺肿瘤疾病的诊断、预防和治疗的新方法。该资助申请的一般假设是：mAAT和E1a基因含有TPA反应元件（TPA），该元件负责通过PKC调节催乳素的表达；这种调节的细胞特异性是通过催乳素激活特定PKC异构体（特别是PKC epsilon）来实现的，它可以激活选择性转录因子（特别是ap - 1）；催乳素增加了E1a的活性形式，从而增加了丙酮酸的氧化。验证这些假设的具体目的是：(1)确定PKC epsilon和激活蛋白i （ap - 1）介导催乳素对mAAT和PDHE1 α表达的调节；(2)确定催乳素是否增加丙酮酸氧化。

Prostate cancer is the second leading cause of cancer deaths in males, and combined with benign prostatic hyperplasia (BPH), represents the leading neoplastic disease in men. In humans, the prostate gland has the unique function of producing and secreting extraordinarily high levels of citrate. These physiology functions of the prostate are regulated by testosterone and prolactin. The lost of the capability to produce citric acid is a characteristic of prostate cancer and is among the first metabolic changes associated with the development of prostate malignancy. Glandular BPH on the other hand is characterized by excessive proliferation of citrate producing secretory epithelial cells and thus an even higher level of citrate that the normal gland. The two key enzymes directly involved in citrate synthesis by prostate epithelial cells are mitochondrial aspartate aminotransferase (mAAT) and pyruvate dehydrogenase (PDH). Both of these enzymes are regulated by testosterone and prolactin. The broad objectives of this grant application are to elucidate the mechanisms by which prolactin regulates expression and activity of these intermediary metabolic enzymes; to elucidate the intracellular signaling pathways involved and to use this information to develop new approaches to the diagnosis, prevention, and treatment of prostate neoplastic disease. The general hypotheses of this grant application are: The mAAT and E1a genes contain a TPA response element (TPA) that is responsible for prolactin regulation of expression via PKC; that the cell specificity of this regulation is achieved by prolactin activation of specific PKC isoforms (particularly PKC epsilon) which activate selective transcription factors (particularly AP-I); and that prolactin increases the active form of E1a which increases pyruvate oxidation. The specific aims proposed to test these hypotheses are (l) to establish that PKC epsilon and activator protein-I (AP-l) mediate prolactin regulation of mAAT and PDHE1 alpha expression; (2) to determine if prolactin increases pyruvate oxidation.