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MK-STYX: A Requisite Gatekeeper to Mitochondrial Function and Death

MK-STYX：线粒体功能和死亡必需的看门人

基本信息

批准号：
8465199
负责人：
Jeffrey Paul MacKeigan
金额：
$ 25.27万
依托单位：
VAN ANDEL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8465199
关键词：
ATP Synthesis Pathway Address Apoptosis Apoptotic Cancer Patient Caspase Cell Death Cell Line Cells Cessation of life Colorectal Colorectal Cancer Complex Coupled Cytotoxic Chemotherapy Data Development Disease Drug Efflux Electron Transport Electrons Gatekeeping Housing Human Genome Kinetics Knowledge Large Intestine Carcinoma Measures Mediating Mitochondria Mitochondrial Proteins Molecular Multidrug Resistance Gene Organelles Oxidative Phosphorylation Patients Pharmaceutical Preparations Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Process Production Proteins Public Health RNA Interference Role Signal Transduction Staging Stimulus Testing Time Xenograft Model base cell type chemotherapeutic agent chemotherapy cohort cytochrome c design efficacy testing efflux pump follow-up in vivo metastatic colorectal neoplastic cell novel overexpression prognostic protein complex response therapeutic target tumor tumor progression

项目摘要

PROJECT SUMMARY/ABSTRACT Chemoresistant metastatic disease presents the most serious threat to cancer patients despite the increased arsenal of targeted therapeutic options available to clinicians. While intense study into late-stage cancer progression has revealed a number of mechanisms that contribute to chemoresistance, little is known about the intracellular signaling mechanisms that desensitize cells to cytotoxic chemotherapy. In an effort to address this knowledge gap, we recently performed a large-scale RNA-interference (RNAi) screen intended to comprehensively identify critical kinases and phosphatases in the human genome that alter or modify tumor cell sensitivity to chemotherapeutic agents. In this RNAi screen, we identified a novel phosphatase, MK-STYX, which potently suppressed the response of tumor cells to a wide variety of chemotherapeutic drugs. Our central hypothesis is that MK-STYX specifically controls mitochondrial function by regulating phosphorylation of the machinery required for ATP synthesis, and thereby serves an essential role in the induction of chemotherapeutic-induced cell death. The objective of this project is to determine how MK-STYX regulates cellular ATP levels, and thus modulates intrinsic apoptosis. We propose the following specific aims to address this hypothesis and to understand its significance in the context of metastatic colorectal carcinoma: (1) Identify the catalytic mechanism of MK-STYX in the mitochondria; (2) Identify the mechanism whereby MK-STYX regulates chemoresistance; (3) Establish the role of MK-STYX in colorectal cancer progression and chemoresistance. Consistent with our central hypothesis, we have shown that loss of MK-STYX increases ATP production. Therefore, we predict that the elevation in cellular ATP due to loss of MK-STYX is sufficient to inhibit apoptosome formation and entry into apoptosis. We have shown that MK-STYX interacts with two additional mitochondrial proteins and we will mechanistically determine the mitochondrial function and the molecular consequences of each of these interactions. We have also shown that loss of MK-STYX expression correlates with colorectal cancer progression. To determine whether loss of MK-STYX mediates chemoresistance in vivo, we will test the efficacy of standard chemotherapies on a colorectal xenograft model using cell lines that demonstrate variable expression of MK-STYX, or have been manipulated to decrease endogenous MK-STYX levels. We will also determine the prognostic significance of MK-STYX protein levels in a cohort of patients with colorectal cancer.

项目摘要/摘要化疗耐药的转移性疾病是对癌症患者最严重的威胁，尽管阿森纳为临床医生提供有针对性的治疗选择。在对晚期癌症进行密集研究的同时进展揭示了许多导致化疗耐药的机制，但人们对此知之甚少使细胞对细胞毒性化疗不敏感的细胞内信号机制。为了努力解决针对这一知识鸿沟，我们最近进行了大规模RNA干扰(RNAi)筛查全面鉴定人类基因组中改变或修饰肿瘤的关键激酶和磷酸酶细胞对化疗药物的敏感性。在这个RNAi筛选中，我们发现了一种新的磷酸酶MK-Styx，它能有效地抑制肿瘤细胞对多种化疗药物的反应。我们的中心假设是MK-Styx通过调节线粒体功能来特异性地控制线粒体的功能三磷酸腺苷合成所需的机械的磷酸化，从而在诱导化疗诱导的细胞死亡。该项目的目标是确定MK-Styx如何调节细胞内的三磷酸腺苷水平，从而调节内在的细胞凋亡。我们提出以下具体目标：阐述这一假说，并了解其在转移性结直肠癌中的意义： (1)确定MK-Styx在线粒体中的催化机制； (2)明确MK-Styx调控化疗耐药的机制； (3)明确MK-Styx在结直肠癌进展和化疗耐药中的作用。与我们的中心假设一致，我们已经表明MK-Styx的丢失增加了ATP的产生。因此，我们预测，由于MK-Styx的缺失而导致的细胞内ATP的升高足以抑制凋亡体的形成和进入细胞凋亡。我们已经证明了MK-Styx与另外两个线粒体蛋白质，我们将从机械上确定线粒体的功能和分子这些互动中的每一个都会产生后果。我们还表明，MK-Styx表达的丧失与伴随着结直肠癌的进展。确定MK-Styx的缺失是否介导了细胞的化疗耐药体内，我们将在结直肠癌异种移植模型上测试标准化疗的有效性，使用的细胞系证明MK-Styx的可变表达，或已被操纵以减少内源性MK-Styx 级别。我们还将确定MK-Styx蛋白水平在一组患者中的预后意义。患有结直肠癌。