Hexokinase 2 and cancer therapy

描述（由申请人提供）： 我们发现，在人前列腺癌和肺癌中，己糖激酶2（HK 2）的表达显着升高，而在正常前列腺和肺细胞中，其表达几乎检测不到。HK 2催化葡萄糖代谢中的第一个关键步骤，并且在糖酵解癌症中高度表达。我们发现，消融癌细胞系中的HK 2显着减弱其在体外和体内的致瘤性。 在这个建议的第一部分，我们将采用小鼠前列腺癌和肺癌模型，模拟人类前列腺癌和肺癌。我们将使用在所有小鼠组织中可以有条件地缺失HK 2的小鼠。这些小鼠将与发展前列腺癌或肺癌的小鼠品系杂交。在肿瘤发展后，HK 2表达将被破坏，以确定HK 2缺陷本身是否可以抑制或逆转肿瘤进展而没有不良生理后果。所提出的实验将克服历史上排除测试这些方法的可行性的主要障碍，因为生殖系HK 2缺失在小鼠中是胚胎致死的，但是我们现在可以使用HK 2flox/flox小鼠在所有成年组织中有条件地缺失HK 2。 在第二部分中，我们将描述HK 2对肿瘤细胞发挥作用的机制。我们将在这些研究中使用来自小鼠模型的癌细胞和人癌细胞。

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.