Hexokinase 2 and cancer therapy

己糖激酶 2 和癌症治疗

基本信息

批准号：
8696773
负责人：
Nissim Hay
金额：
--
依托单位：
JESSE BROWN VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8696773
关键词：
4-Hydroxy-Tamoxifen Ablation Address Adult Affect Alleles Apoptosis Attenuated Biological Assay Cancer Model Cancer cell line Cell Proliferation Cells Chimeric Proteins Commit Complement Data Development Embryo Energy Metabolism Estrogen Receptors Genetic Germ Lines Glycolysis Goals Hexokinase 2 Human In Vitro Injection of therapeutic agent Knockout Mice Ligand Binding Domain Lung Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Mediating Mitochondria Mouse Strains Mus Neoplasms Normal Cell Oncogenic Phenotype Physiological Play Population Predisposition Prostate Prostate carcinoma Protein Isoforms Reliance Rest Role Signal Transduction Tamoxifen Testing Tissues Tumorigenicity Veterans Xenograft procedure addiction cancer cell cancer therapy glucose metabolism hexokinase high risk in vivo inhibitor/antagonist knock-down lung Carcinoma mouse model neoplastic cell prevent research study tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): We found that in human prostate carcinoma and in lung carcinoma hexokinase 2 (HK2) expression is markedly elevated, while in normal prostate and lung cells its expression is hardly detectable. HK2 catalyzes the first committed step in glucose metabolism, and is highly expressed in glycolytic cancers. We found that ablation of HK2 in cancer cell lines significantly attenuate their tumorigenicity both in vitro and in vivo. In the first part of this proposal we wil employ mouse models of prostate carcinoma and lung carcinoma, which emulate human prostate and lung carcinomas. We will employ mice in which HK2 can be conditionally deleted in all mouse tissues. These mice will be crossed with mouse strains that develop either prostate carcinoma or lung carcinoma. Following tumor development, HK2 expression will be disrupted to determine whether HK2 deficiency per se can inhibit or reverse tumor progression without adverse physiological consequences. The proposed experiments would overcome a major obstacle that has historically precluded testing the feasibility of these approach, because germ line HK2 deletion is embryonic lethal in mice, but we can now conditionally delete HK2 in all adult tissues using HK2flox/flox mice. In the second part of this proposal, we will delineate the mechanism by which HK2 exerts its effect on tumor cells. We will employ both cancer cells derived from the mouse models and human cancer cells in these studies.

描述（由申请人提供）：我们发现，在人类前列腺癌和肺癌中，己糖蛋白酶2（HK2）的表达显着升高，而在正常的前列腺和肺细胞中，其表达几乎无法检测到。 HK2催化了葡萄糖代谢的第一个投入步骤，并在糖酵解癌中高度表达。我们发现，癌细胞系中HK2的消融会在体外和体内显着减弱其肿瘤性。在该提案的第一部分中，我们将采用前列腺癌和肺癌的小鼠模型，这些模型模仿了人类前列腺和肺癌。我们将使用在所有小鼠组织中有条件地删除HK2的小鼠。这些小鼠将与产生前列腺癌或肺癌的小鼠菌株交叉。肿瘤发育后，HK2表达将被中断，以确定HK2缺乏本身是否可以抑制或反向肿瘤进展而不会产生不良生理后果。提出的实验将克服一个主要障碍，历史上排除了这些方法的可行性，因为生殖系HK2缺失是小鼠的胚胎致死性，但是现在我们可以使用HK2FLOX/FLOX小鼠在所有成人组织中有条件删除HK2。在该提案的第二部分中，我们将描述HK2对肿瘤细胞的影响的机制。在这些研究中，我们将采用源自小鼠模型和人类癌细胞的癌细胞。