HYPOXIA AND PRX1 IN FINASTERIDE AND SELENIUM INTERVENTION OF PROSTATE CANCER

非那雄胺和硒干预前列腺癌中的缺氧和 PRX1

• 批准号: 7254394
• 负责人: YOUNG-MEE PARK
• 金额: $ 29.19万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7254394
• 关键词: Affect; Androgen Receptor; Apoptosis; Apoptotic; Basement membrane; Biological; Blood Vessels; Blood flow; Cancer Control; Cell Culture System; Cell Survival; Cells; Clonal Expansion; Development; Diffusion; Elevation; Family; Finasteride; Human; Hypoxia; In Vitro; Intervention; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Molecular; Oxidation-Reduction; Oxygen; Partial Pressure; Phenotype; Population; Preventive; Proliferating; Prostate; Protein Family; Proteins; Receptor Signaling; Regulation; Resistance; Selenium; Shunt Device; Signal Transduction; Stress; Testing; Time; Transcriptional Activation; Tumor Oxygenation; Up-Regulation; Xenograft Model; base; cancer cell; human tissue; knock-down; member; novel; pressure; receptor function; response; size; sound; tissue oxygenation; transcription factor; tumor

Hypoxia is a key regulatory microenvironmental factor capable of influencing tumor development and progression. Hypoxia is usually considered a global phenomenon, defined as an overall reduced oxygen availability or partial pressure below critical levels. Tumor vasculature, however, is architecturally and functionally abnormal. The tissue oxygenation/blood flow within a tumor is dynamically changing and heterogeneous at the microenvironmental level. Hypoxia has been proposed to functions as a microenvironmental pressure to select for a fraction of hypoxia-resistant cancer cells with an increased ability to survive and progress. Peroxiredoxins(Prxs) are a newly described family of redox-controlling proteins. Two highly homologous members of this protein family, Prx1 and Prx2, have been shown to affect cell survival and increase stress resistance. However, little is known about the effects of Prx elevation in human cancers, their influence on malignant progression and treatment response, or the regulatory mechanisms. Our preliminary studies provide compelling evidences to support the functional relevance of hypoxiaand Prx1 (but not Prx2) in enhancing the AR function, and suppressing apoptotic signaling. In this study, we will systematically investigate "why"and "how" Prx1 is elevate in prostate cancer cells at the microenvironmentallevel, and study the effect of tissue oxygenation status and Prx1level in modifying the cancer control efficacy of finasteride and selenium. We hypothesize that dynamic changes of tissue oxygenation up-regulate Prx1 expression via redox-sensitive transcription factors, and the dysregulated activation of these transcription factors leads to Prx1 elevation in a subset of prostate cells within a tumor. We also hypothesize that elevated Prx1 confers an aggressive survival phenotype to cells by enhancing AR activity, and reducing oxidative damage and apoptosis. We correspondingly hypothesize that inhibition of Prx1 will increase the AR signaling suppressive and cancer control efficacy of finasteride and selenium. In order to test these hypotheses, four specific aims are proposed. In Aim 1, we will define the molecular basis of Prx1 up-regulation in prostate cancer cells. In Aim 2, we will elucidate the mechanisms whereby Prx1 enhances AR function. In Aim 3 and Aim 4, we will systematically investigate whether and how Prx1 modifies the cancer control efficacy of finasteride and selenium in the context of a hypoxic tumor microenvironment. These studies will provide a sound scientific basis upon which the regulation and function of Prx1 can be elucidated in prostate cancer, enabling the development of novel preventive approaches to inhibit its malignant progression.

缺氧是一个关键的调控微环境因素，能够影响肿瘤的发生和发展