Redox Signaling and Cancer Drug Action

氧化还原信号传导和癌症药物作用

• 批准号: 8637738
• 负责人: GARTH POWIS
• 金额: $ 32.65万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8637738
• 关键词: Angiogenic Factor; Antineoplastic Agents; Apoptotic; Cancer Cell Growth; Cell Death; Cell Survival; Cell physiology; Cells; Clinical Trials; Colorectal Cancer; Correlative Study; Cysteine; Development; Drosophila genus; Drug Targeting; Drug effect disorder; Endoplasmic Reticulum; Family member; Fibroblast Growth Factor 2; Genes; Genetic; Grant; Growth; Growth Factor; Heat shock proteins; Human; In Vitro; Lysophospholipids; Malignant Neoplasms; Mediating; Modification; Molecular Target; Oxidation-Reduction; Pathway interactions; Patients; Phase II Clinical Trials; Phosphorylation; Polyamines; Post-Translational Protein Processing; Proteins; Regulation; Research Design; Role; Signal Pathway; Signal Transduction; Signaling Protein; Small Interfering RNA; Stress; Sulfhydryl Compounds; Testing; Thioredoxin; Translations; Vascular Endothelial Growth Factors; Work; base; cancer cell; drug development; drug discovery; experience; fly; in vivo; inhibitor/antagonist; lysophosphatidic acid; novel; oxidation; pleurotin; response; stress protein; thioredoxin reductase; tumor; tumor growth; Angiogenic Factor; Antineoplastic Agents; Apoptotic; Cancer Cell Growth; Cell Death; Cell Survival; Cell physiology; Cells; Clinical Trials; Colorectal Cancer; Correlative Study; Cysteine; Development; Drosophila genus; Drug Targeting; Drug effect disorder; Endoplasmic Reticulum; Family member; Fibroblast Growth Factor 2; Genes; Genetic; Grant; Growth; Growth Factor; Heat shock proteins; Human; In Vitro; Lysophospholipids; Malignant Neoplasms; Mediating; Modification; Molecular Target; Oxidation-Reduction; Pathway interactions; Patients; Phase II Clinical Trials; Phosphorylation; Polyamines; Post-Translational Protein Processing; Proteins; Regulation; Research Design; Role; Signal Pathway; Signal Transduction; Signaling Protein; Small Interfering RNA; Stress; Sulfhydryl Compounds; Testing; Thioredoxin; Translations; Vascular Endothelial Growth Factors; Work; base; cancer cell; drug development; drug discovery; experience; fly; in vivo; inhibitor/antagonist; lysophosphatidic acid; novel; oxidation; pleurotin; response; stress protein; thioredoxin reductase; tumor; tumor growth

ABSTRACT Thioredoxin family members involved in cellular protein signaling networks provide an important mechanism regulating many aspects of cell function including proliferation and cell survival. Redox signaling involves a protein post translational modification second in importance only to protein phosphorylation. Unlike protein phosphorylation little is known of redox signaling networks in the cell or how they are altered in cancer. The increased expression of one redox signaling protein in particular thioredoxin-1 (Trx-1) has been associated with aggressive tumor growth, decreased apoptotic cell death and decreased patient survival. The hypothesis upon which our studies are based is that redox signaling through thioredoxin family members is an important signaling mechanism that is deranged in cancer and that understanding redox signaling networks in the cancer cell will allow the identification of novel molecular targets for cancer drug discovery and development, and new strategies to treat cancer. We have used Drosophila genetics together with functional genetic siRNA studies in human cancer cells to identify new redox signaling pathways which we will investigate in human cancer cells. We will also investigate the redox regulation of the unfolded protein response (UPR) which is important for maintaining the synthesis of cell survival proteins during stress, including many angiogenic factors important in cancer. We will conduct in vivo antitumor and mechanistic studies of an inhibitor of Trx-1 in colorectal cancer and of a new antitumor inhibitor of thioredoxin reductase we have developed. The overall objective of our studies is to use redox signaling pathways in cancer to identify new molecular targets for cancer drug discovery and development, and to provide new strategies to treat cancer. The work builds upon our past studies of Trx-1 as a cancer drug target which has led to the development of one cancer drug in clinical trial, and seeks to identify new pathways of redox signaling by thioredoxin family members for the identification of molecular targets for cancer drug discovery.

抽象的 参与细胞蛋白信号网络的硫氧还蛋白家族成员提供了重要的机制 调节细胞功能的许多方面，包括增殖和细胞存活。氧化还原信号涉及 蛋白质变化后的修饰仅在蛋白质磷酸化的重要性上。与蛋白质不同 磷酸化对细胞中的氧化还原信号网络或癌症的改变方式知之甚少。这 一种氧化还原信号蛋白的表达增加，特别是硫氧还蛋白-1（TRX-1）已与 随着侵袭性肿瘤的生长，凋亡细胞死亡减少和患者存活降低。假设 我们的研究所基于的是，通过硫氧还蛋白家族成员通过氧化还原信号传导是重要的 在癌症中危险并了解癌症中的氧化还原信号网络的信号传导机制 细胞将允许鉴定新的分子靶标的癌症药物发现和发育，以及新的 治疗癌症的策略。我们已经使用了果蝇遗传学以及功能性遗传siRNA研究 人类癌细胞确定我们将在人类癌细胞中研究的新的氧化还原信号通路。 我们还将研究展开的蛋白质反应（UPR）的氧化还原调节，这对于 在应激过程中维持细胞存活蛋白的合成，包括许多在 癌症。我们将在结直肠癌中进行TRX-1抑制剂的体内抗肿瘤和机械研究 我们已经开发的硫氧还蛋白还原酶的新型抗肿瘤抑制剂。我们的总体目标 研究是使用癌症中的氧化还原信号通路来鉴定癌症药物的新分子靶标 发现和发展，并提供治疗癌症的新策略。这项工作建立在我们的过去 在临床试验中，TRX-1作为癌症药物的研究导致了一种癌症药物的发展 并试图确定硫氧还蛋白家族成员鉴定氧化还原信号的新途径 癌症药物发现的分子靶标。