Role of Zinc in Prostate Carcinogenesis

描述（由申请人提供）：前列腺癌的发生涉及到积聚锌的正常上皮细胞向不积聚锌的恶性细胞的转化。我们证明生理水平的锌可以抑制NFkappaB转录因子的激活，抑制nf - kappab调节的血管生成和转移相关蛋白的表达，包括VEGF、IL-8和MMP-9，并使前列腺癌细胞对雄激素剥夺和细胞毒性药物敏感。NF-kappaB控制的基因有助于恶性转化、耐药和癌症进展到不依赖激素的生长。本研究的总体目的是探讨锌和锌进出口蛋白在前列腺恶性肿瘤发病发展中的作用及其调控机制。我们假设锌输入蛋白（hZIP1和hZIP2）的过表达或锌输出和细胞内分布蛋白（ZnT1至9）的表达减少对NF-kappaB活性、体外和体内前列腺癌细胞的生长和活力有功能影响。特异性目的1将研究锌输入和输出蛋白在正常和转化前列腺细胞中的表达和调节机制。特异性Aim 2将确定通过调节锌进出口蛋白表达增加的细胞内锌积累是否对NF-kappaB活性、前列腺癌细胞的生长和活力有功能影响。特异性Aim 3将确定人锌摄取转运蛋白hZIP1和hZIP2的过表达是否在体内抑制前列腺肿瘤的进展。将亲代前列腺癌细胞或转染了hZIP1或hZIP2的细胞原位注射到裸鼠体内。我们将研究补充锌对肿瘤生长的影响。这些研究将有助于了解锌在前列腺恶性肿瘤发病机制中的作用，因此，可能对前列腺癌的预防和治疗具有重要意义。

DESCRIPTION (provided by applicant): Prostate carcinogenesis involves transformation of zinc-accumulating normal epithelial cells to malignant cells, which do not accumulate zinc. We demonstrate that physiological levels of zinc inhibit activation of NFkappaB transcription factor, suppress expression of NF-kappaB-regulated proteins involved in angiogenesis and metastasis including VEGF, IL-8 and MMP-9 and sensitize prostate cancer cells to androgen deprivation and cytotoxic agents. Genes controlled by NF-kappaB contribute to malignant transformation, drug resistance and cancer progression to hormone-independent growth. The overall objective of the current proposal is to explore the role of zinc and zinc import and export proteins in the pathogenesis and progression of prostate malignancy and mechanisms of their regulation. We hypothesize that overexpression of zinc importers (hZIP1 and hZIP2) or reduced expression of proteins responsible for zinc export and intracellular distribution (ZnT1 through 9) has a functional impact on NF-kappaB activity, growth and viability of prostate cancer cells in vitro and in vivo. Specific Aim 1 will examine the expression and mechanisms of regulation of zinc import and export proteins in normal and transformed prostate cells. Specific Aim 2 will determine whether increased intracellular zinc accumulation via modulation of zinc import and export protein expression has a functional impact on NF-kappaB activity, growth and viability of prostate cancer cells. Specific Aim 3 will determine if overexpression of human zinc uptake transporters hZIP1 and hZIP2 inhibits prostate tumor progression in vivo. Parental prostate cancer cells or cells transfected with either hZIP1 or hZIP2 will be injected orthotopically into nude mice. The effects of dietary zinc supplementation on tumor growth will be examined. The proposed studies will help to understand the role of zinc in the pathogenesis of prostate malignancy and therefore, might have important consequences for the prevention and treatment of prostate cancer.