Targeting Hexokinase II in Chemotherapy

化疗中靶向己糖激酶 II

基本信息

批准号：
7575772
负责人：
JOHN G PASTORINO
金额：
$ 21.84万
依托单位：
UNIV OF MED/DENT NJ-SCH OSTEOPATHIC MED
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-10 至 2012-02-29
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Hexokinase II (HXK II) controls the first step in glycolysis, phosphorylating glucose to glucose-6-phosphate (G-6-P). Cancer cells over-express HXK II with the majority being bound to the mitochondria through an interaction with VDAC-1 (voltage dependent anion carrier), an abundant outer mitochondrial membrane protein (OMM). The enhanced binding of HXK II to mitochondria in cancer cells accelerates the rate of glycolysis, thus providing an ample supply of precursors for amino, nucleic and fatty acid synthesis. Mitochondria have emerged as an important component of the cell death pathway in both apoptosis and necrosis, with the release of mitochondrial intermembrane space proteins being critical in the execution and ultimate demise of cellular viability. Proapoptotic proteins such as Bax, Bid and Bim induce mitochondrial dysfunction, possibly by interacting with VDAC-1, thereby provoking the release of intermembrane space proteins. For this proposal our working hypothesis is that the increased binding of HXK II to mitochondria is critical for providing cancer cells with the necessary metabolic profile for maintaining their accelerated rate of proliferation. Additionally, HXK II binding to mitochondria aids in the survival and resistance of cancer cells to chemotherapeutic agents by preventing proapoptotic proteins such as Bax, Bim and Bid from inducing mitochondrial dysfunction. The localization of HXK II to mitochondria is controlled in part by the activity of the PBR and glycogen synthase kinase 3P (GSKP). These hypotheses are supported by the preliminary results demonstrating the ability of recombinant HXK II to prevent Bax from binding to and releasing cytochrome c from isolated mitochondria and the enhanced sensitivity exhibited by transformed cells to a range of chemotherapeutic agents upon the detachment of mitochondrial bound HXK II. Inhibition of PBR mediated cholesterol uptake and phosphorylation of VDAC-1 by GSK3? resulted in a detachment of HXK II from mitochondria with the subsequent development of enhanced sensitivity to chemotherapy induced cell death. The general goals of this project are to provide a deeper understanding of the mechanism(s) by which mitochondrial bound HXK II increases the proliferation and survival of cancer cells and to elucidate how HXK II binding to mitochondria is regulated and maintained, with the goal of exploiting the binding of HXK II to mitochondria as an anti-cancer target.

描述（由申请人提供）：己糖激酶II（HXK II）控制糖酵解，磷酸化葡萄糖至6-磷酸葡萄糖（G-6-P）的第一步。通过与VDAC-1（电压依赖性阴离子载体）的相互作用（一种丰富的线粒体外膜蛋白（OMM））的相互作用，癌细胞过表达HXK II与线粒体结合。 HXK II与癌细胞中线粒体的结合增强了糖酵解速率，从而为氨基，核和脂肪酸合成提供了充足的前体供应。线粒体已成为细胞死亡和坏死中细胞死亡途径的重要组成部分，线粒体间膜间空间蛋白的释放对于细胞生存能力的执行和最终消亡至关重要。促凋亡蛋白（例如Bax，BID和BIM）可能通过与VDAC-1相互作用，从而诱导线粒体功能障碍，从而引起膜间空间蛋白的释放。对于这一提议，我们的工作假设是，HXK II与线粒体的结合增加对于为癌细胞提供维持其加速增殖速率的必要代谢特征至关重要。此外，通过防止促凋亡蛋白（例如BAX，BIM和BID和BID）诱导线粒体功能障碍，HXK II与线粒体结合有助于癌细胞对化学治疗剂的存活和耐药性。 HXK II在线粒体中的定位部分由PBR和糖原合酶激酶3P（GSKP）的活性控制。这些假设得到了初步结果的支持，证明了重组HXK II防止Bax从分离的线粒体中结合并释放细胞色素C的能力，并且在线粒体结合HXK II的分离后，转化细胞对一系列化学治疗剂表现出增强的敏感性。 GSK3抑制PBR介导的胆固醇摄取和VDAC-1的磷酸化？导致HXK II脱离线粒体，随后发展对化学疗法诱导的细胞死亡的敏感性增强。该项目的一般目标是提供对线粒体结合的HXK II增加癌细胞的增殖和存活的机制的更深入的了解，并阐明HXK II与线粒体与线粒体结合的结合方式，并以利用HXK II与Mitochondira的靶向为抗抗体。