Role of Zinc in Prostate Carcinogenesis

锌在前列腺癌发生中的作用

• 批准号: 7410058
• 负责人: VLADIMIR M KOLENKO
• 金额: $ 28.48万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-15 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7410058
• 关键词: Anchorage-Independent Growth; Androgens; Animal Model; Apoptosis; Apoptotic; Benign Prostatic Hypertrophy; Carrier Proteins; Cells; Clinical; Condition; Cultured Cells; Cytotoxic agent; Data; Development; Dietary Zinc; Disease regression; Drug resistance; Epithelial; Epithelial Cells; Exhibits; Family; Family member; Gelatinase B; Genes; Growth; Hormones; Human; IL8 gene; In Vitro; Laboratories; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of prostate; NF-kappa B; Neoplasm Metastasis; Nude Mice; Oncogenes; PC3 cell line; Pathogenesis; Physiological; Prevention; Property; Prostate; Prostatic; Prostatic Neoplasms; Protein Export Pathway; Protein Overexpression; Proteins; Rate; Regulation; Role; Specimen; Supplementation; Tumor Tissue; Vascular Endothelial Growth Factors; Zinc; angiogenesis; cancer cell; carcinogenesis; cell growth; cell transformation; deprivation; in vivo; member; mouse model; protein expression; research study; soft tissue; transcription factor; tumor; tumor growth; tumor progression; uptake; zinc-binding protein

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.

描述（由申请人提供）：前列腺癌发生涉及锌蓄积的正常上皮细胞转化为不蓄积锌的恶性细胞。我们证明，生理水平的锌抑制NF-κ B转录因子的激活，抑制参与血管生成和转移的NF-κ B调节蛋白（包括VEGF、IL-8和MMP-9）的表达，并使前列腺癌细胞对雄激素剥夺和细胞毒性剂敏感。由NF-κ B控制的基因有助于恶性转化，耐药性和癌症进展到非依赖性生长。目前的建议的总体目标是探讨锌和锌的进出口蛋白在前列腺恶性肿瘤的发病机制和进展及其调节机制的作用。我们假设锌进口商（hZIP 1和hZIP 2）的过度表达或负责锌输出和细胞内分布的蛋白质（ZnT 1至9）的表达减少对体外和体内前列腺癌细胞的NF-κ B活性、生长和活力具有功能性影响。具体目标1将检查正常和转化前列腺细胞中锌输入和输出蛋白的表达和调节机制。具体目标2将确定通过调节锌输入和输出蛋白表达增加的细胞内锌积累是否对前列腺癌细胞的NF-κ B活性、生长和活力具有功能性影响。具体目标3将确定人锌摄取转运蛋白hZIP 1和hZIP 2的过表达是否抑制体内前列腺肿瘤进展。将亲本前列腺癌细胞或用hZIP 1或hZIP 2转染的细胞原位注射到裸鼠中。将检查膳食锌补充剂对肿瘤生长的影响。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产生重要影响。

项目成果

Zinc chelation induces rapid depletion of the X-linked inhibitor of apoptosis and sensitizes prostate cancer cells to TRAIL-mediated apoptosis.

• DOI: 10.1038/cdd.2008.106
• 发表时间: 2008-11
• 期刊: CELL DEATH AND DIFFERENTIATION
• 影响因子: 12.4
• 作者: Makhov, P.;Golovine, K.;Uzzo, R. G.;Rothman, J.;Crispen, P. L.;Shaw, T.;Scoll, B. J.;Kolenko, V. M.
• 通讯作者: Kolenko, V. M.

Depletion of intracellular zinc increases expression of tumorigenic cytokines VEGF, IL-6 and IL-8 in prostate cancer cells via NF-kappaB-dependent pathway.

• DOI: 10.1002/pros.20810
• 发表时间: 2008-09-15
• 期刊: PROSTATE
• 影响因子: 2.8
• 作者: Golovine, Konstantin;Uzzo, Robert G.;Makhov, Peter;Crispen, Paul L.;Kunkle, David;Kolenko, Vladimir M.
• 通讯作者: Kolenko, Vladimir M.

Overexpression of the zinc uptake transporter hZIP1 inhibits nuclear factor-kappaB and reduces the malignant potential of prostate cancer cells in vitro and in vivo.

• DOI: 10.1158/1078-0432.ccr-08-0455
• 发表时间: 2008-09-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Golovine K;Makhov P;Uzzo RG;Shaw T;Kunkle D;Kolenko VM
• 通讯作者: Kolenko VM

Transcriptional regulation of the major zinc uptake protein hZip1 in prostate cancer cells.

• DOI: 10.1016/j.gene.2008.10.015
• 发表时间: 2009-02-15
• 期刊: GENE
• 影响因子: 3.5
• 作者: Makhov, Peter;Golovine, Konstantin;Uzzo, Robert G.;Wuestefeld, Torsten;Scoll, Benjamin J.;Kolenko, Vladimir M.
• 通讯作者: Kolenko, Vladimir M.

Reversal of epigenetic silencing of AP-2alpha results in increased zinc uptake in DU-145 and LNCaP prostate cancer cells.

AP-2α 表观遗传沉默的逆转导致 DU-145 和 LNCaP 前列腺癌细胞中锌的摄取增加。

• DOI: 10.1093/carcin/bgr212
• 发表时间: 2011
• 期刊: Carcinogenesis
• 影响因子: 4.7
• 作者: Makhov,PeterB;Golovine,KonstantinV;Kutikov,Alexander;Canter,DanielJ;Rybko,VeraA;Roshchin,DmitryA;Matveev,VsevolodB;Uzzo,RobertG;Kolenko,VladimirM
• 通讯作者: Kolenko,VladimirM