Zinc Transport Relationships in Prostate Cancer Cells

描述(由申请人提供)：众所周知，前列腺癌(PCA)与正常前列腺或良性前列腺增生症(BPH)相比，其特征是柠檬酸盐和锌水平显著下降。有强有力的证据表明，锌蓄积的改变在调节前列腺上皮细胞的柠檬酸代谢中起着重要作用，与前列腺癌的发生和发展有关。我们的主要目标是建立正常前列腺细胞锌蓄积的机制和调控；确定与恶性肿瘤的发生和发展有关的锌蓄积丢失的改变；建立恢复恶性和癌前前列腺癌细胞锌蓄积的机制；利用这些信息开发诊断、治疗甚至预防前列腺癌的新方法。正常的前列腺腺上皮细胞具有在体内积累和分泌最高水平的柠檬酸和锌的主要功能和能力。我们最近确定了锌和柠檬酸之间的重要联系，即锌抑制(线粒体)间乌头酸酶活性和柠檬酸氧化产生柠檬酸的前列腺上皮细胞。在前列腺癌中，由于丧失了积累高水平锌的能力，前列腺癌细胞经历了从积累锌的正常细胞到柠檬酸氧化的恶性细胞的转变。这种代谢转化发生在恶性肿瘤的早期，是恶性肿瘤进展的一个明显要求。因此，丢失积累锌的能力，从而改变柠檬酸代谢的机制，是前列腺癌的关键关系。该提案的具体目的是：1.建立ZIP1促进锌从血浆进入细胞的机制。2.确定参与催乳素和睾酮调节的ZIP1基因调控区的结构。3.证实ZIP1基因的表达改变了前列腺细胞(PC-3和LNCaP)的致瘤性。4.明确ZIP1表达降低和锌蓄积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.