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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：
8268519
负责人：
Jeffrey Paul MacKeigan
金额：
$ 26.88万
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/8268519
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.

项目总结/文摘