Hexokinase-2 bound to mitochondria: cancer's stygian link to the "Warburg Effect" and a pivotal target for effective therapy.
Hexokinase-2 bound to mitochondria: cancer's stygian link to the "Warburg Effect" and a pivotal target for effective therapy.
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DOI：
10.1016/j.semcancer.2008.11.006
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发表时间：
2009-02
影响因子：
14.5
通讯作者：
Pedersen PL
中科院分区：
文献类型：
--
作者：
Mathupala SP;Ko YH;Pedersen PL
恶性肿瘤最常见的代谢标志，即，“瓦尔堡效应”是它们甚至在氧气存在下也以高速率将葡萄糖代谢成乳酸的倾向。这种常见癌症表型中的关键参与者是尿醛结合的己糖激酶[Bustamante E，Pedersen PL.培养的大鼠肝癌细胞的高有氧糖酵解：线粒体己糖激酶的作用。Proc Natl Acad Sci USA 1977;74（9）：3735−9; Bustamante E，Morris HP，Pedersen PL.肿瘤细胞的能量代谢。需要一种具有线粒体结合倾向的己糖激酶。J Biol Chem 1981;256（16）：8699−704]。现在，在世界各地的诊所中，这种突出的表型形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是表现出“瓦尔堡效应”的癌症中表达的主要结合的己糖激酶同种型。这包括大多数转移并杀死人类宿主的癌症。通过将自身固定在线粒体外膜上，HK-2还有助于使癌细胞永生化，逃避产物抑制，并优先获得新合成的ATP以磷酸化葡萄糖。后一种情况将这种必需的营养素作为葡萄糖-6-P捕获在肿瘤细胞内，其中一些被作为碳前体，以帮助促进新癌细胞的产生，而大部分被转化为离开细胞的乳酸。由此产生的酸性可能会阻止免疫反应，同时为周围组织的入侵做好准备。随着“瓦尔堡效应”作为大多数临床癌症的突出表型和“代谢靶向”作为合理的治疗策略的重新出现和接受，许多实验室正在关注代谢物进入或退出步骤。一个显著的成功故事[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]是使用小分子3-溴丙酮酸（3-BP），其通过靶向HK-2和线粒体ATP酶体两者选择性地进入并破坏动物中的大肿瘤的细胞。这导致非常快速的ATP消耗和肿瘤破坏，而不会对动物造成伤害。本文综述了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点的潜力。
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.
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影响因子：
4.8
作者：
Ardehali, H;Yano, Y;Granner, DK
通讯作者：
Granner, DK
DOI：
10.1016/0006-291x(85)90948-9
发表时间：
1985-01-01
影响因子：
3.1
作者：
JOHANSSON, T;BERREZ, JM;NELSON, BD
通讯作者：
NELSON, BD
DOI：
10.1016/j.bbrc.2004.09.047
发表时间：
2004-11-05
影响因子：
3.1
作者：
Ko, YH;Smith, BL;Pedersen, PL
通讯作者：
Pedersen, PL
影响因子：
9.9
作者：
DICHIRO, G;DELAPAZ, RL;WOLF, AP
通讯作者：
WOLF, AP
影响因子：
11.5
作者：
Cao, Xianhua;Bloomston, Mark;Sun, Duxin
通讯作者：
Sun, Duxin