Hexokinase 2 and cancer therapy

己糖激酶 2 和癌症治疗

基本信息

批准号：
10661677
负责人：
Nissim Hay
金额：
$ 56.25万
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/10661677
关键词：
A kinase anchoring protein Ablation Acceleration 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 Inhibition of Cancer Cell Growth 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 Kinase 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.

癌细胞在代谢上与正常匹配细胞不同，这表明癌细胞中葡萄糖代谢的高率。癌症中葡萄糖代谢的高率细胞至少部分是由于明显的己糖激酶（HK2）表达的诱导在大多数正常细胞中未表达。大多数正常的成年组织和细胞表达己糖酶1 （HK1），但是当它们转化为癌细胞时，它们开始表达高水平的HK2。因此，HK2 可能是癌细胞的标志，可以针对癌症治疗。多年来，我们提供概念的遗传证据，表明可以在小鼠中系统地删除HK2以抑制癌症没有不利后果。我们表明HK2缺乏抑制了启动和在肺癌，乳腺癌，肝癌和前列腺的小鼠模型中维持癌症癌症。同样，人类癌细胞中HK2的诱导型抑制了肿瘤形成后的肿瘤。在此赠款申请中，我们将调查新颖的HK2活动以前没有探索。这些活动包括：（i）HK2的新型月光功能，独立于其葡萄糖激酶活性。这项活动可以决定某些人的稳定性与细胞存活，氧化还原调控相关的蛋白质，例如MCL1，NRF2和蜗牛，和EMT和转移。（ii）HK2在糖基化，肿瘤微环境中的作用和免疫疗法。（iii）HK2通过组蛋白乳糖化对基因表达的影响。