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Hexokinase 2 and cancer therapy

己糖激酶 2 和癌症治疗

基本信息

批准号：
10299101
负责人：
Nissim Hay
金额：
$ 49.05万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10299101
关键词：
A kinase anchoring protein Ablation Address Adult Affect Applications Grants Binding Breast cancer metastasis Cell Survival Cells Cyclic AMP-Dependent Protein Kinases Cytotoxic T-Lymphocytes Gene Expression Genetic Glucose Glucose-6-Phosphate Glycogen Synthase Kinase 3 Glycolysis Goals Hexokinase 2 Histones Human Immunotherapy MCL1 gene Maintenance Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of lung Malignant neoplasm of prostate Mammary Neoplasms Mediating Metabolic Metabolism Mus Neoplasm Metastasis Normal Cell Normal tissue morphology Nutrient Oxidation-Reduction Phosphorylation Phosphotransferases Positron-Emission Tomography Protein Subunits Proteins Regulation Resistance Role Scaffolding Protein Tissues adverse outcome cancer cell cancer therapy checkpoint therapy fluorodeoxyglucose positron emission tomography glucose metabolism glycosylation hexokinase knock-down malignant breast neoplasm mouse model neoplasm immunotherapy neoplastic cell novel programmed cell death ligand 1 recruit response scaffold success targeted cancer therapy tumor tumor growth tumor microenvironment tumor progression tumorigenesis

项目摘要

Cancer cells are metabolically different from normal matching cells, and this is manifested by the high rate of glucose metabolism in cancer cells. The high rate of glucose metabolism in cancer cells is, at least in part, due to the marked induction of hexokinase (HK2) expression, which is not expressed in most normal cells. Most normal adult tissues and cells express hexokinase 1 (HK1), but when they convert into cancer cells, they start expressing high levels HK2. Thus, HK2 could be a hallmark of cancer cells and could be targeted for cancer therapy. Over the years we provided genetic proofs of concept that HK2 can be systemically deleted in mice to inhibit cancer without adverse consequences. We showed that HK2 deficiency inhibited both initiation and maintenance of cancer in mouse models of lung cancer, breast cancer, liver cancer, and prostate cancer. Likewise, inducible knockdown of HK2 in human cancer cells inhibited the growth of tumors after tumor formation. In this grant application we will investigate novel HK2 activities that were not previously explored. These activities include: (i) A novel moonlighting function of HK2, independently of its glucose kinase activity. This activity could determine the stability of certain proteins such as MCL1, NRF2, and SNAIL that are associated with cell survival, redox regulation, and EMT and metastasis respectively. (ii) A role of HK2 in glycosylation, tumor microenvironment and immunotherapy. (iii) The effect of HK2 on gene expression through histone lactylation.

癌细胞在代谢上不同于正常的配对细胞，这体现在癌细胞的葡萄糖代谢率很高。癌症中的高糖代谢率细胞至少部分是由于己糖激酶(HK2)表达的显著诱导，这是在大多数正常细胞中不表达。大多数正常成人组织和细胞都表达己糖激酶1 (HK1)，但当它们转化为癌细胞时，它们开始表达高水平的HK2。因此，香港2 可能是癌细胞的标志，并可能成为癌症治疗的靶点。多年来，我们提供了HK2可在小鼠体内系统缺失以抑制癌症的概念的遗传学证据而不会有不良后果。我们发现，HK2的缺乏抑制了启动和肺癌、乳腺癌、肝癌和前列腺癌小鼠模型中癌症的维持癌症。同样，在人类癌细胞中可诱导的HK2基因敲除抑制了人癌细胞的生长肿瘤形成后的肿瘤。在这项拨款申请中，我们会调查新的HK2活动，包括以前都没有被勘探过。这些活动包括：(I)香港天文台一项新颖的月光功能，与其葡萄糖激酶活性无关。这种活性可以决定某些物质的稳定性 MCL1、NRF2和Snail等与细胞存活、氧化还原调节、 EMT和转移分别为。(Ii)HK2在糖基化、肿瘤微环境中的作用和免疫疗法。(Iii)HK2通过组蛋白乳糖化作用对基因表达的影响。