Zinc Transport Relationships in Prostate Cancer Cells

描述（由申请方提供）：众所周知，与正常前列腺或良性前列腺增生（BPH）相比，前列腺癌（PCa）的特征始终是柠檬酸盐和锌水平显著降低。强有力的证据表明，改变锌蓄积在调节前列腺上皮细胞柠檬酸盐代谢中具有重要作用，与前列腺恶性肿瘤的发生和进展相关。我们的广泛目标是建立正常前列腺细胞中锌积累的机制和调节;确定与恶性肿瘤的发病机制和进展相关的锌积累损失的改变;建立恶性和癌前前列腺细胞中锌积累的恢复机制;利用这些信息开发诊断、治疗甚至预防前列腺恶性肿瘤的新方法。正常前列腺上皮细胞具有在体内积累和分泌最高水平的柠檬酸盐和锌的主要功能和能力。我们最近建立了锌和柠檬酸盐之间的重要联系;即，锌抑制产生柠檬酸盐的前列腺上皮细胞的（线粒体）m-乌头酸酶活性和柠檬酸盐氧化。在PCa中，前列腺细胞经历从锌积累、柠檬酸盐产生的正常细胞到柠檬酸盐氧化的恶性细胞的转化，这是由于丧失了积累高锌水平的能力。这种代谢转化发生在恶性肿瘤的早期，并且是恶性肿瘤进展的明显要求。因此，与锌积累能力丧失有关的机制（这允许柠檬酸盐代谢的改变）是前列腺恶性肿瘤的关键关系。该提案的具体目标是：1。建立ZIP 1促进锌从血浆转运到细胞的机制。2.确定ZIP 1基因调控区的结构，该基因赋予催乳素和睾酮调节。3.确定ZIP 1表达改变改变前列腺细胞（PC-3和LNCaP）的致瘤性。4.为了确定ZIP 1表达减少和锌积累减少是否是前列腺癌恶性细胞的特征。

DESCRIPTION (provided by applicant): It is well established that prostate cancer (PCa), as contrasted with normal prostate or benign prostatic hyperplasia (BPH), is consistently characterized by dramatic decreases in citrate and zinc levels. Strong and compelling evidence exists that implicate a significant role of altered zinc accumulation in the regulation of citrate metabolism of prostate epithelial cells associated with the development and progression of prostate malignancy. Our broad objectives are to establish the mechanism and regulation of zinc accumulation in normal prostate cells; to determine the alterations that accounts for the loss of zinc accumulation associated with the pathogenesis and progression of malignancy; to establish mechanisms to restore zinc accumulation in malignant and pre-malignant prostate cells; to use this information in the development of new approaches to the diagnosis, treatment and perhaps prevention of prostate malignancy. Normal prostate glandular epithelial cells have the major function and capability of accumulating and secreting the highest levels of both citrate and zinc in the body. We recently established the important link between zinc and citrate; i.e., zinc inhibits (mitochondrial) m-aconitase activity and citrate oxidation of citrate-producing prostate epithelial cells. In PCa, prostate cells undergo a transformation from zinc-accumulating, citrate-producing sane cells to citrate oxidizing malignant cells, due to the lost ability to accumulate high zinc levels. This metabolic transformation occurs early in malignancy and is an apparent requirement for progression of the malignancy. Thus, the mechanism involved in the lost ability to accumulate zinc, which permits the alteration in citrate metabolism, is a key relationship in prostate malignancy. The specific aims of the proposal are: 1. To establish the mechanism by which ZIP1 facilitates the transport of zinc from plasma into the cell. 2. To determine the structure of the regulatory region of the ZIP1 gene that confers prolactin and testosterone regulation. 3. To establish that altered expression of ZIP1 alters the tumorigenicity of prostate cells (PC-3 and LNCaP). 4. To determine if decreases expression of ZIP1 and decreased zinc accumulation are characteristics of malignant cells in prostate cancer.