Hexokinase 2 and cancer therapy

描述(由申请人提供)： 我们发现己糖激酶2(HK2)在前列腺癌和肺癌中的表达显著升高，而在正常前列腺和肺细胞中几乎检测不到它的表达。HK2催化葡萄糖代谢的第一步，在糖酵解性癌症中高表达。我们发现，在体外和体内，切除癌细胞系中的HK2显著降低了它们的致瘤性。在这项建议的第一部分，我们将使用前列腺癌和肺癌的小鼠模型，它们模仿人类的前列腺癌和肺癌。我们将使用可以在所有小鼠组织中有条件地删除HK2的小鼠。这些小鼠将与患前列腺癌或肺癌的小鼠品系杂交。随着肿瘤的发展，HK2的表达将被干扰，以确定HK2缺乏本身是否可以抑制或逆转肿瘤的进展，而不会产生不利的生理后果。拟议的实验将克服历史上排除测试这些方法可行性的主要障碍，因为生殖系HK2缺失对小鼠胚胎是致命的，但我们现在可以使用HK2FLOX/FLOX小鼠有条件地删除所有成人组织中的HK2。在这项建议的第二部分，我们将描述HK2对肿瘤细胞发挥作用的机制。在这些研究中，我们将同时使用来自小鼠模型的癌细胞和人类癌细胞。

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.