Hexokinase 2 and cancer therapy

 描述(由PI提供)： 癌细胞在代谢上不同于正常的配对细胞，这表现在癌细胞的葡萄糖代谢率很高。由于癌细胞的高有氧糖酵解率区别于正常细胞，它被利用于正电子发射断层扫描(PET)中的葡萄糖类似物氟2-脱氧葡萄糖(FDG)，用于体内癌细胞的选择性成像。PET是在注射[18F]-FDG之后使用的，然后被糖酵解癌细胞摄取，并被己糖激酶磷酸化形成FDG-6-磷酸，然后可以被PET检测到。FDG的磷酸化保留并在细胞内积累标记的FDG，因为与磷酸化的葡萄糖不同，它不能进一步用于糖酵解。因此，FDG-PET扫描的成功可以解释为与正常细胞相比，癌细胞中己糖激酶的活性更高。这一观察提出了一个问题：如果利用更高活性的己糖激酶选择性地为癌细胞成像，为什么不能利用它来选择性地靶向癌细胞。这可能是具有挑战性的，因为己糖激酶催化葡萄糖代谢的第一步，对每个活细胞都是关键的。然而，有几种己糖激酶亚型。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己糖激酶2(HK2)。因此，HK2的高表达区分了癌细胞和正常细胞，并决定了FDG-PET扫描的成功。为了评估HK2对癌症发展的需求，以及其消融是否可以选择性地靶向癌细胞，在目前的资助期内，我们培育了可以在肿瘤发病前后有系统地删除HK2的小鼠。通过使用这个小鼠模型，我们提供了一个概念的遗传学证据，即全身抑制HK2对肺癌和乳腺癌具有良好的耐受性和治疗作用。在这项拨款建议中，我们将进一步探讨在组织和细胞水平上，消融HK2对乳腺癌和前列腺癌的进展和转移的新观察和后果。

 DESCRIPTION (provided by PI): Cancer cells are metabolically different from normal matching cells, and this is manifested by the high rate of glucose metabolism in cancer cells. Because high rate of aerobic glycolysis distinguishes cancer cells from normal cells it is exploited for the selective imaging of cancer cells in vivo through the utilization of the glucose analog fluoro-2-deoxyglucose (FDG) in positron emission tomography (PET). PET is used following injection of [18F]-FDG, which is then being taken by glycolytic cancer cells and is phosphorylated by hexokinase to form FDG-6-phosphate, which can then be detected by PET. The phosphorylation of FDG retains and accumulates the labeled FDG inside cells because unlike phosphorylated glucose it cannot be further utilized in glycolysis. Thus, the success of the FDG-PET scan could be explained by the higher activity of hexokinase in cancer cells when compared to normal cells. This observation raises the question; if higher activity of hexokinase is exploited to selectively image cancer cell, why it cannot be exploited to selectively target the cancer cells. This could be challenging because hexokinase, which catalyzes the first committed step in glucose metabolism is critical for every living cell. However, there are several hexokinase isoforms. Most normal adult tissues and cells express hexokinase 1 (HK1), but when they convert into cancer cells they start expressing high levels of hexokinase 2 (HK2). Thus, the high expression of HK2 distinguishes cancer cells from normal cells, and determines the success of FDG-PET scan. To assess the requirement of HK2 for cancer development and whether its ablation could selectively target the cancer cells, in the current funding period, we have generated mice in which we could systemically delete HK2 before or after tumor onset. By employing this mouse model we provided a genetic proof of concept that systemic HK2 inhibition is well-tolerated and therapeutic for lung and breast cancer. In this grant proposal we will further explore new observations and consequences of HK2 ablation in and breast and prostate cancer progression and metastasis both at the organismal and cellular levels.