Hexokinase 2 and cancer therapy

癌细胞在代谢上不同于正常的匹配细胞，这表现在癌细胞的代谢上。 癌细胞中葡萄糖代谢率高。癌症中的高葡萄糖代谢率 至少部分是由于己糖激酶（HK2）表达的显著诱导， 在大多数正常细胞中不表达。大多数正常成人组织和细胞表达己糖激酶1 (HK1)但当它们转化为癌细胞时，它们开始表达高水平的HK2。因此，HK2 可能是癌细胞的标志，也可能是癌症治疗的目标。多年来我们 提供了概念的遗传学证据，即HK2可以在小鼠中全身缺失以抑制癌症 没有不良后果。我们发现，HK2缺陷抑制启动和 在肺癌、乳腺癌、肝癌和前列腺癌的小鼠模型中维持癌症 癌同样，在人类癌细胞中HK2的可诱导敲低抑制了肿瘤细胞的生长。 肿瘤形成后。在这项资助申请中，我们将调查新颖的HK2活动， 以前没有探索过。这些活动包括：（i）HK2的新兼职功能， 独立于其葡萄糖激酶活性。这种活性可以决定某些化合物的稳定性。 与细胞存活，氧化还原调节， 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通过组蛋白乳酸化对基因表达的影响。

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.