Redox Signaling and Cancer Drug Action

摘要 硫氧还蛋白家族成员参与细胞蛋白信号网络提供重要机制 调节细胞功能的许多方面，包括增殖和细胞存活。氧化还原信号涉及一种 蛋白质翻译后修饰的重要性仅次于蛋白质磷酸化。与蛋白质不同 对于细胞中的氧化还原信号网络或它们在癌症中是如何改变的，人们知之甚少。这个 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) 随着肿瘤的侵袭性生长，减少了凋亡细胞的死亡，降低了患者的存活率。假说 我们的研究基于的是，通过硫氧还蛋白家族成员传递氧化还原信号是一个重要的 癌症中错乱的信号机制以及对癌症中氧化还原信号网络的理解 细胞将允许识别新的分子靶点，用于癌症药物的发现和开发，以及新的 治疗癌症的策略。我们已经将果蝇遗传学和功能遗传siRNA研究结合在一起 以确定新的氧化还原信号通路，我们将在人类癌细胞中进行研究。 我们还将研究未折叠蛋白反应(UPR)的氧化还原调节，这对 在应激过程中维持细胞存活蛋白的合成，包括许多重要的血管生成因子 癌症。我们将在体内进行TRX-1抑制剂在结直肠癌中的抗肿瘤作用和机制研究 以及我们开发的一种新的硫氧还蛋白还原酶抗肿瘤抑制剂。我们的总体目标是 研究是利用癌症中的氧化还原信号通路来确定抗癌药物的新分子靶点 发现和发展，并提供治疗癌症的新策略。这项工作是以我们的过去为基础的 Trx-1作为抗癌药物靶点的研究导致了一种抗癌药物的临床试验开发， 并试图通过硫氧还蛋白家族成员识别氧化还原信号的新途径 抗癌药物发现的分子靶点。

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.