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首页> 外文期刊>Seminars in cancer biology >Hexokinase-2 bound to mitochondria: cancer's stygian link to the 'Warburg Effect' and a pivotal target for effective therapy.
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Hexokinase-2 bound to mitochondria: cancer's stygian link to the 'Warburg Effect' and a pivotal target for effective therapy.

机译：Hexokinase-2与线粒体结合：癌症的触角与“ Warburg效应”有关，是有效治疗的关键靶标。

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摘要

The most common metabolic hallmark of malignant tumors, i.e., the "Warburg effect" is their propensity to metabolize glucose to lactic acid at a high rate even in the presence of oxygen. The pivotal player in this frequent cancer phenotype is mitochondrial-bound hexokinase [Bustamante E, Pedersen PL. High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase. Proc Natl Acad Sci USA 1977;74(9):3735-9; Bustamante E, Morris HP, Pedersen PL. Energy metabolism of tumor cells. Requirement for a form of hexokinase with a propensity for mitochondrial binding. J Biol Chem 1981;256(16):8699-704]. Now, in clinics worldwide this prominent phenotype forms the basis of one of the most common detection systems for cancer, i.e., positron emission tomography (PET). Significantly, HK-2 is the major bound hexokinase isoform expressed in cancers that exhibit a "Warburg effect". This includes most cancers that metastasize and kill their human host. By stationing itself on the outer mitochondrial membrane, HK-2 also helps immortalize cancer cells, escapes product inhibition and gains preferential access to newly synthesized ATP for phosphorylating glucose. The latter event traps this essential nutrient inside the tumor cells as glucose-6-P, some of which is funneled off to serve as carbon precursors to help promote the production of new cancer cells while much is converted to lactic acid that exits the cells. The resultant acidity likely wards off an immune response while preparing surrounding tissues for invasion. With the re-emergence and acceptance of both the "Warburg effect" as a prominent phenotype of most clinical cancers, and "metabolic targeting" as a rational therapeutic strategy, a number of laboratories are focusing on metabolite entry or exit steps. One remarkable success story [Ko YH, Smith BL, Wang Y, Pomper MG, Rini DA, Torbenson MS, et al. Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP. Biochem Biophys Res Commun 2004;324(1):269-75] is the use of the small molecule 3-bromopyruvate (3-BP) that selectively enters and destroys the cells of large tumors in animals by targeting both HK-2 and the mitochondrial ATP synthasome. This leads to very rapid ATP depletion and tumor destruction without harm to the animals. This review focuses on the multiple roles played by HK-2 in cancer and its potential as a metabolic target for complete cancer destruction.
机译：恶性肿瘤最常见的代谢标志，即“ Warburg效应”是即使在有氧的情况下，它们也易于将葡萄糖高速率代谢为乳酸。在这种常见的癌症表型中，关键的是线粒体结合的己糖激酶[Bustamante E，Pedersen PL。培养中大鼠肝癌细胞的高氧糖酵解：线粒体己糖激酶的作用。美国国家科学院院刊1977; 74（9）：3735-9; Bustamante E，Morris HP，Pedersen PL。肿瘤细胞的能量代谢。需要具有线粒体结合倾向的己糖激酶形式。生物化学杂志1981; 256（16）：8699-704]。现在，在全世界的诊所中，这种突出的表型构成了最常见的癌症检测系统之一的基础，即正电子发射断层扫描（PET）。值得注意的是，HK-2是在具有“ Warburg效应”的癌症中表达的主要结合己糖激酶同工型。这包括转移和杀死人类宿主的大多数癌症。通过将自身定位在线粒体外膜上，HK-2还可以使癌细胞永生，逃避产物抑制作用，并优先获得新合成的ATP来磷酸化葡萄糖。后一种事件将这种基本营养物以葡萄糖-6-P的形式捕获在肿瘤细胞内，其中一部分被漏出以充当碳前体，从而有助于促进新癌细胞的产生，同时许多转化为乳酸并从细胞中排出。在准备周围组织进行侵袭时，产生的酸性可能会阻止免疫反应。随着“ Warburg效应”作为大多数临床癌症的显着表型以及“代谢靶向”作为一种合理的治疗策略的出现和接受，许多实验室正致力于代谢物的进入或退出步骤。一个非凡的成功故事[Ko YH，Smith BL，Wang Y，Pomper MG，Rini DA，Torbenson MS等。晚期癌症：在所有情况下均使用3-溴丙酮酸盐疗法消除ATP根除。 Biochem Biophys Res Commun 2004; 324（1）：269-75]是利用3-溴丙酮酸小分子（3-BP）通过靶向HK-2和HBP选择性进入和破坏动物大肿瘤细胞的方法。线粒体ATP合酶体。这导致非常快速的ATP消耗和肿瘤破坏，而没有对动物造成伤害。这篇综述重点介绍了HK-2在癌症中的多种作用及其作为完全破坏癌症的代谢靶标的潜力。

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