Targeting Hexokinase II in Chemotherapy

化疗中靶向己糖激酶 II

• 批准号: 8080827
• 负责人: JOHN G PASTORINO
• 金额: $ 17.01万
• 依托单位: UNIV OF MED/DENT NJ-SCH OSTEOPATHIC MED
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-10 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8080827
• 关键词: Accounting; Amino Acids; Anions; Apoptosis; Binding; Cancerous; Cell Death; Cells; Cholesterol; Development; Exhibits; Fatty Acids; Glucose; Glucose-6-Phosphate; Glycogen (Starch) Synthase; Glycogen Synthase Kinases; Glycolysis; Goals; Hexokinase 2; Malignant Neoplasms; Mediating; Metabolic; Mitochondria; Mitochondrial Membrane Protein; Necrosis; Normal Cell; Nucleic Acids; Outer Mitochondrial Membrane; Pathway interactions; Phosphorylation; Proteins; Recombinants; Resistance; Signal Pathway; Voltage-Dependent_Anion_Channel-1; Work; cancer cell; cell transformation; chemotherapeutic agent; chemotherapy; cytochrome c; mitochondrial dysfunction; prevent; uptake; voltage

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）控制糖酵解的第一步，将葡萄糖磷酸化为葡萄糖-6-磷酸（G-6-P）。癌细胞过度表达HXK II，大多数通过与VDAC-1（电压依赖性阴离子载体），一种丰富的线粒体外膜蛋白（OMM）的相互作用结合到线粒体上。癌细胞中HXK II与线粒体的结合增强，加快了糖酵解的速度，从而为氨基酸、核酸和脂肪酸的合成提供了充足的前体。线粒体已成为细胞凋亡和坏死死亡途径的重要组成部分，线粒体膜间隙蛋白的释放对细胞活力的执行和最终死亡至关重要。促凋亡蛋白如Bax、Bid和Bim可能通过与VDAC-1相互作用诱导线粒体功能障碍，从而引发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与线粒体结合的增加对于为癌细胞提供维持其加速增殖所需的代谢谱至关重要。此外，与线粒体结合的HXK II通过阻止Bax、Bim和Bid等促凋亡蛋白诱导线粒体功能障碍，帮助癌细胞存活和抵抗化疗药物。HXK II在线粒体中的定位部分受PBR和糖原合成酶激酶3P （GSKP）活性的控制。这些假设得到了初步结果的支持，这些结果表明重组HXK II能够阻止Bax与分离的线粒体结合并释放细胞色素c，并且在脱离与HXK II结合的线粒体后，转化细胞对一系列化疗药物的敏感性增强。PBR对胆固醇摄取和VDAC-1磷酸化的抑制作用导致HXK II从线粒体分离，随后对化疗诱导的细胞死亡的敏感性增强。本项目的总体目标是更深入地了解线粒体结合的HXK II增加癌细胞增殖和存活的机制，阐明HXK II与线粒体的结合是如何被调节和维持的，目的是利用HXK II与线粒体的结合作为抗癌靶点。