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 Table of Contents  
Year : 2018  |  Volume : 4  |  Issue : 2  |  Page : 54-58

The contribution of hexokinase 2 in glioma

1 Department of Experimental Surgery, The Second Affiliated Hospital, Air Force Medical University, Xi'an, Shaanxi, China
2 Department of Neurosurgery, University of Massachusetts Medical School, Worcester, WA, USA
3 Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA

Date of Submission09-Apr-2018
Date of Acceptance12-Apr-2018
Date of Web Publication27-Apr-2018

Correspondence Address:
Dr. Yanyang Tu
Department of Experimental Surgery, The Second Affiliated Hospital, Air Force Medical University, Xi'an 710038, Shaanxi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ctm.ctm_11_18

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Glioma is the most frequent malignant neoplasm of the central nervous system with high recurrence and extremely poor prognosis. Hexokinase 2 (HK2) is the key enzyme in Warburg effect that has been proved to promote tumorigenesis and is found highly expressed in several tumors. However, the HK2 function in glioma was reported only in a few studies. In this review, we will summarize the changes in the energy metabolism in glioma and the critical function of HK2 in the process. Further, the recent research progress and perspective of HK2 in the diagnosis and treatment of glioma will be discussed.

Keywords: Energy metabolism, glioma, hexokinase 2, Warburg effect

How to cite this article:
Liu H, Yang H, Wang X, Tu Y. The contribution of hexokinase 2 in glioma. Cancer Transl Med 2018;4:54-8

How to cite this URL:
Liu H, Yang H, Wang X, Tu Y. The contribution of hexokinase 2 in glioma. Cancer Transl Med [serial online] 2018 [cited 2019 Jan 16];4:54-8. Available from: http://www.cancertm.com/text.asp?2018/4/2/54/231375

  Introduction Top

Glioma is the most common malignant tumor of the central nervous system, accounting for 50%–60% of all intracranial tumors, with very poor prognosis, despite the postsurgical multimodal therapy, radiotherapy, and chemotherapy.[1],[2],[3] The mean 5-year patient survival is reported to be 20%–30% in glioma and a mere 1% in glioblastoma.[4],[5] Similar to many other malignant tumors, Warburg Effect is one of the most important biological characteristics of glioma, characterized by its low degree of differentiation, rapid proliferation, and being able to maintain cell metabolic activity in both normoxic and hypoxic environment, which is proposed to be the cause of tumorigenesis. Considering the crucial role of Warburg effect, the key proteins involved in the process can serve as molecular targets for the treatment of gliomas.[6],[7],[8]

Hexokinase 2 (HK2) is the key enzyme that catalyzes the first step of glycolysis. It binds to the N-terminus of voltage-dependent anion channel (VDAC) to form the HK2-VDAC complex, which can not only inhibit mitochondria-induced apoptosis by reducing the release of cytochromes C but also promote the glycolysis by suppressing the negative feedback of glucose-6-phosphate (G-6P).[9] Furthermore, the complex can also increase the synthesis of ATP, to promote glycolysis of tumor cells in the presence of oxygen, providing energy and substrate for biomacromolecules.[10] HK2 is considered as the ideal target for tumor therapy due to its key role in tumorigenesis. Several HK2 inhibitors have been explored for the treatment of cancers. However, there are no effective treatments targeting HK2, except fluorodeoxyglucose-positron emission tomography (FDG-PET), which is used in both diagnosis and treatment of cancer so far.[11] Therefore, it is important to explore and develop a new HK2-targeted therapeutic approach for treating cancer.

  Abnormal Energy Metabolism of Glioma Top

Glioma is the most common malignant tumor of the central nervous system, the common treatment of which is surgery followed by chemotherapy and radiotherapy. Despite this multimodal approach, the prognosis of glioma is still very poor. The 5-year survival of glioma patients is reported to be < 30%, and as for the glioblastoma patients, the mean survival is just about half a year.

Different from normal cells, the glioma cells are with features of genomic instability and altered metabolism and dysregulated metabolic pathways.[12] Abnormal metabolism in glioma includes alterations in glucose, amino acids, fats, and nucleic acids. As a result of this, the glioma cells gain the ability to grow in a stressful environment, resist apoptosis, and escape immunological surveillance, which supports migration and invasion of glioma cells.[13],[14],[15],[16]

Three conditions are needed for the rapid proliferation of glioma cells: (1) sufficient ATP to provide energy; (2) the increased macromolecular synthesis for cell proliferation; and (3) stable redox equilibrium for cellular stability. The metabolism of carbohydrates, proteins, fats, and nucleic acids is not only needed for the proliferation of glioma cells but also for their adaption to the actualin vivo environment.[17],[18] Cancer cells need to balance their energy consumption to keep up their growth, survival, proliferation, and long-term maintenance.

As early as 1920s, it has already been found that abnormal metabolism exists in all those tumors demonstrating increased glucose uptake and fermentation of glucose to lactate, despite the presence of normal mitochondria within tumor cells. It was called as Warburg effect. However, the importance of abnormal metabolism in the development of tumors has not been realized until the physical examination technologies, like PET technology, were developed.[19],[20],[21] Currently, it is believed that the metabolic abnormality of tumor can benefit its survival. First, it can provide a variety of substrates for the synthesis of macromolecules such as ATP, nicotinamide adenine dinucleotide phosphate (NADPH), and acetyl CoA. Second, the tumor cells can obtain more space since they consume more nutrients, leaving the surrounding normal cells hungry. Meanwhile, the tumor cells can also promote their own proliferation through releasing the oxygen free radicals. Here, we will begin with the Warburg effect for further explanation.

  Warburg Effect in Glioma Top

Due to the rapid proliferation and low differentiation of glioma cells, in addition to relatively slower growth of blood vessel, ischemia and hypoxia frequently occur. Therefore, it is crucial for glioma cells to maintain cellular metabolism even in hypoxia. Different from normal cells, most glioma cells prefer glycolysis, which is less effective than mitochondrial oxidation to produce energy. Although oxygen and mitochondria are not directly involved in this mechanism, the rate of glycolysis in glioma is usually 200 times higher than normal tissue, even in the presence of sufficient oxygen. This phenomenon is known as aerobic glycolysis, which is considered to be the tumor-specific Warburg effect,[22] and this effect is also thought to be the radical cause of tumorigenesis. The efficiency of glycolysis in producing energy is lower compared to the normal oxidative phosphorylation process. It is proved that the synthesis of macromolecules as the intermediate products, but not ATP, is the main purpose of oxidative phosphorylation in glioma.[23] The reasons for success of glioma through glycolysis could be as follows: (1) glioma can continue to grow even in low oxygen environment through glycolysis, thus overcoming the slower rate of angiogenesis; (2) lactic acid, the product of glycolysis, can acidify the surrounding microenvironment and thus inhibit the anti-immune factors promoting the invasion of glioma; (3) NADPH, an another important product of glycolysis and an antioxidant, can effectively resist the adverse influence of environmental and chemotherapeutic drugs on glioma by maintaining the suitable redox state; (4) the glycolytic intermediates, such as 5-phosphate ribose and 6-phosphate glucose, as the substrates for the synthesis of macromolecules, are crucial for the growth and proliferation of glioma cells.[24],[25],[26]

As for the molecular mechanism of Warburg effect, it is reported that the activation of oncogenes such as c-Myc, the inactivation of tumor suppressor genes such as p53, and the activation of transcription factors such as hypoxia-inducible factor-1 alpha may be involved in the upregulation of Warburg effect. Moreover, mitochondrial DNA mutations and the inactivation of oxidative phosphorylation-related enzyme may also be related to the glycolysis. Few studies have also shown that the inflammatory response, hypoxic stress, metabolism and oxidative stress, carcinogenic factors, and many other factors can contribute to glycolysis process.[27],[28] The mechanism of glycolysis in glioma has not been fully revealed of its complexity. Therefore, the key proteins involved in the glycolysis of glioma have become the important targets of molecular therapy in glioma.

  Hexokinase 2 and Glioma Top

Hexokinases, the key committed enzymes in the first step of the glycolysis, have four isoenzymes in humans, including HK1, HK2, HK3, and HK4, with different gene localizations and functional characteristics. The four isoenzymes of HK are distributed in different tissues in humans: HK1 is mainly distributed in the brain tissue; HK2 mainly exits in the fat and skeletal muscle; HK3 mainly exists in the liver, kidney, and intestine; and HK4 only exists in the liver and pancreas. The ratio of the four types of HK also changes with age, even in the same tissue.[29],[30],[31],[32] It is shown that, among all the four HK isoenzymes, HK2 is most closely related to malignant tumors and is highly expressed in various tumor tissues and models. Here, we will explore the contribution of HK2 in glioma in detail.

The structural characteristics of hexokinase 2 and its abnormal expression in glioma

The human HK2 gene is located on chromosome 2q13 and consists of 2751 bases, containing 18 exons and 17 introns, of which the promoter region is about 4 kb. As for HK2 protein, it contains 917 amino acid residues, with the molecular weight of about 100 kDa.[33] There is little HK2 in healthy human tissues, except in fat and skeletal muscle. Earlier, HK2 was found to be expressed at high level in gastric cancer, colorectal cancer, and some other tumors. With the progress in various examination technologies, research has confirmed high-level HK2 expression in more and more tumors and was closely associated with tumor malignancy.[34] Our studies have also shown that HK2 was highly expressed in glioma tissues and cell lines, and the rate of expression increased with the WHO grades of glioma.[35]

The promoter of HK2 gene accounts for this abnormally high HK2 expression in glioma. Studies have shown that glucose, insulin cAMP, insulin, and few other factors can upregulate the activity of HK2 promoter, induce p53 mutation, and activate hypoxic state. Glucose combined with hypoxia is the most potent activator of HK2 promoter, although just glucose itself can activate the HK2 promoter in malignant tumors.[5],[36],[37] The increased expression of HK2 can be supported by its own protein functions as follows: (1) HK2 has higher glucose-binding capacity compared to glucose kinase; (2) HK2 can resist the suppression of G-6P through obtaining the priority of mitochondria ATP since it can bind to VDAC; (3) different from HK1, both binding sites of HK2 have the catalytic function. Consequently, the high binding capacity of the substrate, the low inhibition of intermediate product, and high catalytic ability of HK2 make it express at high level in glioma.[38],[39]

Contribution of hexokinase 2 and its chaperone in the development of glioma

It is known that HK2 alone is not responsible for the development of glioma.[40],[41] Four proteins play important roles in this process, which are glucose transporter (GLUT), mitochondrial outer membrane protein (VDAC), mitochondrial ATP synthase, and the adenine nucleotide transporter.[42] GLUT is responsible for the transport of glucose into the cell, which is the most important substrate of HK2. VDAC can form HK2-VDAC complex by binding with HK2 and then promote glycolysis. VDAC itself is highly expressed in many tumors. In addition to the intracellular ratio of glucose/G-6P and ADP/ATP, lactate levels, pH, and some other factors, a large number of tumor suppressor genes, oncogenes, and signal transduction pathways, such as Akt/PI3K pathway, are also involved in the interaction between HK2 and VDAC. Glioma cells can produce large amounts of G-6P through the assistance of the four chaperones, which is not only an important intermediate in the glycolysis but also provides substrates for mitochondrial TCA cycle and pentose phosphate pathway.[43],[44]

Contribution and mechanism of hexokinase 2 in glioma

In addition to the function of HK2-VDAC complex in the development of glioma, it is also shown that HK2 itself can also resist the glioma cell apoptosis. HK2 can interact with Bid, Bax, and so on, which are the antiapoptotic components of Bcl2, ANT, and CypD family proteins, to form mitochondrial membrane permeability transition pore complex that can stabilize mitochondrial outer membrane and inhibit mitochondria from releasing cytochrome c, which is known to induce apoptosis.[45] Besides, the association between HK2 and mitochondria in resisting cell apoptosis is also recognized as a key factor in survival of glioma cells.[46],[47] The combination can effectively play this resistance as the downstream factor of Akt pathway and the separation of HK2 from mitochondria plays the converse role.[39],[48],[49],[50],[51],[52] Studies have shown that the induction of exogenous HK2 could resist the apoptosis induced by hypoxia and HK2 has the protective effect in glioma cells indeed.[53],[54],[55],[56] HK2 was also reported to play crucial role in the radioresistance of glioma through PI3K/Akt signaling pathway.[57],[58],[59],[60],[61] The possible mechanism is shown in [Figure 1].
Figure 1: The possible mechanism of hexokinase 2/PI3K/Akt/GSK3β/CyclinD1 signaling pathway in radioresistance

Click here to view

  Perspective of Hexokinase 2 in the Treatment of Glioma Top

HK2 is considered to be a promising target in glioma therapy due to its crucial contribution in Warburg effect and resistance of apoptosis in glioma cells. However, there are only a few effective treatments targeting HK2, in addition to FDG-PET that have been used both in the diagnosis and treatment of glioma. Here, we will brief a few potential strategies for treating glioma, targeting HK2.

Treatment of glioma targeting hexokinase 2 itself

Hexokinase 2 inhibitors

As a class of antitumor metabolism drugs, HK2 inhibitors have showed a certain application value. For example, 2-deoxyglucose (2-DG), an analogue of glucose, can competitively inhibit the activity of HK2, and the HK2 phosphorylated 2-DG can also inhibit the activity of HK2 through the negative feedback mechanism. Another promising therapeutic inhibitor for HK2 is 3-bromopyruvate, which has a potent inhibitory effect on HK2 and its clinical application has also been explored.[62]

Hexokinase 2 small interfering RNA

RNA interference (RNAi) is an effective tool for studying the regulation of gene expression. It has high sequence specificity and can silence specific gene expression without affecting the expression of other genes. Many studies have achieved preferable progress in the research of potential therapeutic application of HK2 small interfering RNA. The studies have also successfully interfered the expression of HK2 bothin vitro andin vivo through RNA interference technology and obtained expected achievements.[63],[64]

Inhibition of Warburg effect by blocking hexokinase 2 and mitochondria

Some studies have attempted to disrupt the binding of HK2 and VDAC, thus tampering the resistance to apoptosis, for the treatment of glioma. For this, some compounds that could disrupt this binding were selected such as bifonazole, methylated jasmonate, and clotrimazole, all of which have the same nitrogen terminus as HK2. All of these compounds were found to be able to induce apoptosis in tumor cells and thus pose a promise toward the treatment of glioma.[65],[66]

  Conclusion Top

The abnormal energy metabolism is one of the most important characters of glioma, and the understanding of metabolism of glioma has changed significantly with the progress in the understanding of the related oncogenes. HK2, a committed enzyme in the first step of the Warburg effect and with a high level of expression in glioma, can resist the apoptosis by binding to VDAC and increase the radio-resistance of glioma. Considering the key role of HK2 in glioma, it is possible to achieve great progress in drug development targeting HK2. Such achievements also prove that HK2 is an ideal target for molecular therapy of glioma, with broad clinical application prospects, providing a new and effective strategy and direction in the treatment of glioma.

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Conflicts of interest

There are no conflicts of interest.

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