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The possible mechanism of hexokinase 2/PI3K/Akt/GSK3β/CyclinD1 signaling pathway in radioresistance
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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....
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Daphnetin (7,8-dihydroxycoumarin), a natural coumarin compound, has shown antitumor and energy metabolism regulatory activities. However, the effects of daphnetin on cell proliferation, migration, and glucose metabolism in colorectal cancer (CRC) cells remains unknown. In this study, the effects of daphnetin on CRC cell proliferation, migration, an...
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... Consistently, the enzymes PI3K and pAkt involved in the signaling pathway that promotes GBM cell survival showed significantly higher levels in U87 cells than in NHAs ( Figure 1G,H). HK-II, which catalyzes the rate-limiting first step of glycolysis and thus has a key role in energy and glucosemediated lipid metabolism, is one of the multiple enzymes transcriptionally regulated by Akt [21] and is up-regulated in several types of tumors, including GBM [36,37]. Accordingly, HK-II was also more expressed in U87 cells as compared to NHAs ( Figure 1K), which indicates the importance of the glycolytic metabolism for GBM cells. ...
Modulation of lipid metabolism is a well-established cancer hallmark, and SCD1 has been recognized as a key enzyme in promoting cancer cell growth, including in glioblastoma (GBM), the deadliest brain tumor and a paradigm of cancer resistance. The central goal of this work was to identify, by MS, the phospholipidome alterations resulting from the silencing of SCD1 in human GBM cells, in order to implement an innovative therapy to fight GBM cell resistance. With this purpose, RNAi technology was employed, and low serum-containing medium was used to mimic nutrient deficiency conditions, at which SCD1 is overexpressed. Besides the expected increase in the saturated to unsaturated fatty acid ratio in SCD1 silenced-GBM cells, a striking increase in polyunsaturated chains, particularly in phosphatidylethanolamine and cardiolipin species, was noticed and tentatively correlated with an increase in autophagy (evidenced by the increase in LC3BII/I ratio). The contribution of autophagy to mitigate the impact of SCD1 silencing on GBM cell viability and growth, whose modest inhibition could be correlated with the maintenance of energetically associated mitochondria, was evidenced by using autophagy inhibitors. In conclusion, SCD1 silencing could constitute an important tool to halt GBM resistance to the available treatments, especially when coupled with a mitochondria disrupter chemotherapeutic.
... Generalised decrease in hexokinase activity was observed in all the organs examined in the infected mice. Similar alteration in hexokinase activity in different organs as a result of disease conditions have been observed by many authors with evidence of alteration in glucose metabolism [37,38,39,40,41,42,43,44,45]. The decrease in the hexokinase activity in this study could not be linked to the feedback inhibition by the glycolytic pathways products in the organs since severe reduction in the serum glucose was also observed in this study. ...
Trypanosoma brucei brucei depends on mammalian host glucose for survival and establishment of infection. The interference with host glucose results in disturbance of pathways for glucose metabolism and their enzymes. Therefore, this study tried to examine the relationship between untreated Trypanosoma brucei brucei infection and the host hexokinase activity in selected organs that depend on glucose for their normal biological and biochemical functions. The mice for this study were grouped into two: control (uninfected) and infected group. Baseline values for PCV, serum glucose and protein; hexokinase activity and protein concentration in the liver, kidney, heart and brain were obtained for each group. The infected group was intraperitoneally inoculation by 1× 10 4 parasites/mice and monitor for the presence of Trypanosoma brucei brucei from the second day post infection. The same parameters were collected again on days 4 and 11 before the death of the infected group. Protein was determined by colorimetric method using Bradford reagent. PCV was analysed using a sysmex haematology analyser while hexokinase activity was measured spectrophotometrically by a coupled reaction with glucose-6-phosphate dehydrogenase at 340 nm. The result of this study showed that untreated Trypanosoma brucei brucei infection resulted in decrease in PCV, serum glucose, hexokinase activity in the liver, kidney, heart and brain but increase in serum protein. In conclusion, untreated Trypanosoma brucei brucei infection resulted in reduction in host liver, kidney, brain and heart hexokinase activity which probably deprived them of the needed energy and may be the cause of early death in untreated trypanosomiasis.
... Unlike hexokinase-1, the hexokinase-2 enzyme is mainly encoded in skeletal and cardiac muscles, and its expression is induced by insulin. Hexokinase-2 is encoded via HK2, which is located in chromosome 2p13 and has 18 exons [60,61]. ...
Clopidogrel is an antiplatelet drug commonly used to prevent coagulation. This review aimed to investigate the effect of polymorphisms of G6PD, GCLC, GCLM, GSS, GST, GSR, HK and GLRX genes on clopidogrel during phase II metabolism through exploring previous studies. The results revealed that low glutathione plasma levels caused by several alleles related to these genes could affect the bioactivation process of the clopidogrel prodrug, making it unable to inhibit platelet aggregation perfectly and thus leading to severe consequences in patients with a high risk of blood coagulation. However, the study recommends platelet reactivity tests to predict clopidogrel efficacy rather than studying gene mutations, as most of these mutations are rare and other nongenetic factors could affect the drug’s efficacy.
... Hexokinase-2 encoded via HK-2 gene located in chromosome number 2 at band p13 and has 18 exons. [52] ...
Clopidogrel is one of the thienopyridine antiplatelet drugs commonly used as a prophylactic medication to prevent coagulation in vessels and cardiovascular events. The molecule of clopidogrel is metabolized in the liver via phase-I and phase-II metabolism pathways. The sulfenic acid clopidogrel metabolite undergoes phase-II metabolism through conjugation with glutathione by the glutathione-s-transferase (GST) to form a glutathione conjugate of clopidogrel (inactive metabolite). A glutaredoxin enzyme removes the glutathione conjugated with clopidogrel to form cis-thiol-clopidogrel. This review focused on the polymorphisms of genes related to phase-II metabolism during the clopidogrel bioactivation process. Overall, no well-controlled studies were done about the relationship between the clopidogrel bioactivation process and genes related to phase-II metabolism's enzymes. Nevertheless, some polymorphisms of G6PD, GCLC, GCLM, GSS, GST, GSR, HK, and GLRX genes could be responsible for clopidogrel resistance due to low glutathione conjugate or glutaredoxin plasma levels. Studies needed to be concerned with the relationship between clopidogrel resistance and phase-II metabolism issues in the near future.
... Hexokinase activity in both soluble and particulate fractions of mammalian tissue extracts has been recognized for over 50 years (Liberti, & Locasale, 2016), where the particulate fraction can be largely accounted for by specific HKI and HKII binding to the OMM at mitochondrial contact sites. This binding is both dynamic and regulated (Wilson, 2003) and involves specific interaction between the outer membrane of mitochondria OMM voltage-dependent anion channel (VDAC) and hydrophobic mitochondrial binding domains found in the aminoterminus of HKI and HKII, but not HKIII or GK (Azoulay, Israelson, Abu-hamad, & Shoshan, 2004;Hay, & Sonenberg 2014;Liu, Yang, Wang, & Tu, 2018). Mammalian VDAC directly participates in the specific binding of mitochondrial hexokinases to the OMM (Ritter, Wahl, Freund, Genzel, & Reichl, 2010;Fontaine, Sanchez, Camarda, & Lagunoff, 2015;Jin, Meihong, Dagang, & Yujin, 2016). ...
Dengue virus hijacks the host cellular mechanism to propagate and survive during viral infection, in which the central carbon mechanism plays a crucial role to upregulate DENV infection through the increase of human hexokinase II (HKII) activity. Since the enzyme governs the glycolytic pathway, it has potentials as a target for anti-dengue (DENV) drug development. In this study, the production of human hexokinase II protein has been enhanced by using bacterial system for anti-dengue therapeutic purpose. The HKII gene was cloned into pET28b vector and transformed into the E. coli strain BL21 (DE3) for HKII expression. In order to obtain soluble recombinant HKII in an active form, we optimized protein expression under specific conditions at 18°C for 19 hours using Terrific Broth media, in the presence of 0.5 mM isopropyl-2-D-thiogalactopyranoside (IPTG). The pET28b-HKII construct expressed in BL21(DE3) system exhibited adequate protein expression, thus, this construct was subsequently proceeded to purification process. The expressed protein was purified to homogeneity by a combination of Immobilized Metal Ion Affinity Chromatography (IMAC)and size exclusion chromatography (SEC), resulting in pure, active bacterially-expressed HKII with a specific activity of 56. 67U.mg-1. The amount of HKII obtained from 2 L culture is 80 mg, with a yield percentage of 10.5%. Hence in this study, human HKII has successfully been cloned and expressed as a soluble protein that can be utilized for further therapeutic studies.
... HK1 is widely expressed in almost all mammalian tissues and highly expressed in the brain, HK2 is expressed in insulinsensitive tissues such as adipose tissue and skeletal muscle, HK3 is expressed at low levels in most tissues, and HK4 expression is limited to the pancreatic B cells and liver. (40) Amongst these, HK2 is the most upregulated isoform in many tumors including glioma, (40)(41)(42) prostate cancer, (43) ovarian, (44) hepatocellular, (45) and head and neck cancers. (46) The mitochondrial receptor for HK2, the voltage dependent anion channel (VDAC), facilitates the binding of HK2 to the mitochondria, forming HK2-VDAC complex. ...
... (11) The HK2-VDAC complex enhances glycolysis via suppressing the negative feedback of glucose 6-phosphate and enhances ATP production to promote aerobic glycolysis in the presence of oxygen. (41) Furthermore, role of HK2 is also observed at the mRNA/posttranscriptional level in prostate cancer. Clinical and experimental findings have implicated that genetic loss of both Pten and p53 in prostate epithelial cells play a causal role in prostate cancer. ...
Under oxygen availability, normal cells undergo mitochondrial oxidative phosphorylation to metabolize glucose and yield up to 36 ATPs per glucose molecule for cellular functions; and, undergo non-oxidative metabolism (glycolysis) under hypoxic and proliferating conditions to yield 2 ATP per glucose. These cells metabolize glucose to pyruvate via glycolysis followed by conversion of pyruvate to lactate via lactate dehydrogenase. However, cancer cells have the ability to undergo glycolysis and ferment glucose to lactate regardless of oxygen availability; a phenomenon first addressed by Otto Warburg and called, ”Warburg effect”. Numerous glycolytic genes/proteins have been identified in tumors; that include glucose transporter 1 (GLUT1), hexokinase 2 (HK2), pyruvate kinase-M2 splice isoform (PKM2), and lactate dehydrogenase (LDH-A). Histone deacetylase sirtuin 6 (SIRT6), an epigenetic regulator, is highly expressed in various cancers. SIRT6 plays an important role in Warburg effect by regulating many glycolytic genes. Loss of SIRT6 enhances tumor growth via enhancing glycolysis. This review is mainly concerned with exploring the most recent advances in understanding the roles of the metabolic genes (GLUT1, HK2, PKM2, and LDH-A) and the epigenetic regulator SIRT6 in cancer metabolism and how SIRT6 can modulate these metabolic genes expression and its possible use as a therapeutic target for cancer treatment.
... In the glycolytic pathway of human cell, glucose is converted to GLC-6-P and this process is governed by human hexokinase II (HKII), which is present in skeletal and cardiac muscle, as well as insulin-sensitive tissues such as adipocytes [5]. Inside the human's body, the specific hexokinase isoform has specific functions on a particular cell; for example human hexokinase I (HKI) is a regulatory enzyme of both brain and blood cell glycolysis [6] and HKII is the principle regulator for cancer cell and tumor cell [7]- [9]. On the other hand, hexokinase IV (HKIV), also referred as glucokinase, plays a regulatory role in carbohydrate metabolism in the beta cells of the pancreatic and controls insulin release, similarly glucagon release in the alpha cells of liver [10]. ...
Human hexokinase II (HKII) is one of the key enzymes in the glycolytic pathway. It has been postulated that HKII is a potential target for anti-dengue (DENV) drug development, as well as involved in cancer and tumor cell growth. In this work, the human hexokinase II (HKII) gene was cloned into pETite N-His SUMO vector and transformed into the E.coli strain HI-control 10G for the propagation of clones. Two different expression hosts, E.coli HI-controlTM BL21 (DE3) and BL21 (DE3) pLysS were used to optimize HKII expression. In order to obtain the soluble recombinant HKII in a functional form, we optimized protein expression at three different temperatures; 17°C, 25°C and 37°C, at 24 hours incubation time. The soluble protein was expressed in the presence of 0.5 mM isopropyl-2-D-thiogalactopyranoside (IPTG) in TB media at 17°C for 24 hrs. The expressed protein was then purified to homogeneity by a combination of Immobilized Metal Ion Affinity Chromatography (IMAC), size exclusion chromatography (SEC) and ion-exchange chromatography (IEX), resulting in pure bacterially-expressed HK2. Taken together, this study has successfully produced soluble bacterially-expressed human HKII that can be utilized for further therapeutic studies.
Despite technological advancement, there is no 100% effective treatment against metastatic cancer. Increasing resistance of cancer cells towards chemotherapeutic drugs along with detrimental side effects remained a concern. Thus, the urgency in developing new anticancer agents has been raised. Anticancer peptides have been proven to display potent activity against a wide variety of cancer cells. Several mode of actions describing their cytostatic and cytotoxic effect on cancer cells have been proposed which involves cell surface binding leading to membranolysis or internalization to reach their intracellular target. Understanding the mechanism of action of these anticancer peptides is important in achieving full therapeutic success. In the present article, we discuss the anticancer action of peptides accompanied by the mechanisms underpinning their toxicity to cancer cells.
