Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 -- 2686 2023-04-13 19:38:46 |
2 This is an adapted and abridged version. Meta information modification 2686 2023-04-13 19:42:15 | |
3 format correction -1 word(s) 2685 2023-04-14 04:32:37 |

Video Upload Options

Do you have a full video?

Confirm

Are you sure to Delete?
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Farooq, Z.; Ismail, H.; Bhat, S.A.; Layden, B.T.; Khan, M.W. Role of Hexokinases in Metabolic Reprogramming. Encyclopedia. Available online: https://encyclopedia.pub/entry/43047 (accessed on 13 June 2024).
Farooq Z, Ismail H, Bhat SA, Layden BT, Khan MW. Role of Hexokinases in Metabolic Reprogramming. Encyclopedia. Available at: https://encyclopedia.pub/entry/43047. Accessed June 13, 2024.
Farooq, Zeenat, Hagar Ismail, Sheraz Ahmad Bhat, Brian T. Layden, Md. Wasim Khan. "Role of Hexokinases in Metabolic Reprogramming" Encyclopedia, https://encyclopedia.pub/entry/43047 (accessed June 13, 2024).
Farooq, Z., Ismail, H., Bhat, S.A., Layden, B.T., & Khan, M.W. (2023, April 13). Role of Hexokinases in Metabolic Reprogramming. In Encyclopedia. https://encyclopedia.pub/entry/43047
Farooq, Zeenat, et al. "Role of Hexokinases in Metabolic Reprogramming." Encyclopedia. Web. 13 April, 2023.
Role of Hexokinases in Metabolic Reprogramming
Edit

The role of hexokinases in metabolic reprogramming in cancer is multifaceted and pivotal for the altered metabolic phenotype observed in cancer cells. Hexokinases, a group of enzymes responsible for catalyzing the first step of glycolysis, play a critical role in regulating glucose metabolism in cancer cells. In cancer, hexokinases are upregulated and exhibit distinct isoform preferences. Hexokinases facilitate the Warburg effect, a hallmark metabolic alteration in cancer cells characterized by increased glycolysis and decreased oxidative phosphorylation by promoting high glucose consumption and ATP production. Furthermore, hexokinases also participate in other metabolic pathways, such as the pentose phosphate pathway and mitochondrial metabolism, contributing to the rewiring of cancer cell metabolism. The overexpression of hexokinases in cancer cells supports the high bioenergetic and biosynthetic demands of rapidly proliferating cells and confers survival advantages by modulating cellular redox status and apoptosis. The dysregulation of hexokinases in cancer cells presents a promising target for cancer therapy. Understanding their role in metabolic reprogramming provides crucial insights into cancer metabolism and potential therapeutic strategies.

cancer metabolism HKDC1 hexokinases glucose metabolism

1. Regulation of Hexokinase Activity

HK isoforms have different catalytic and regulatory properties. HK1 is activated by high inorganic phosphate levels (Pi) and inhibited by the product G6P. Therefore, a cellular milieu with a high ratio of Pi/G6P because of high rates of ATP utilization favors glycolysis through HK1 activity for the generation of ATP [1]. One of the best examples to illustrate this is the reversal of the G6P-induced inhibition of HK1 by inorganic phosphate (Pi), which leads to the evasion of the G6P-induced feedback inhibition of glucose phosphorylation and favors its ubiquitous expression since glycolysis is a primary requirement of all mammalian cells [1][2][3].
On the other hand, HK2 lacks this antagonizing response by Pi, and instead, Pi adds to the inhibition caused by G6P in the case of HK2 [4]. This feature favors HK2 activity in metabolically active tissues such as skeletal muscles to replenish glycogen synthesis following muscle contraction. Existing literature suggests an anabolic role for HK2 [4][5]. Additionally, a wealth of literature agrees with an anabolic role for HK2, funneling G6P to synthesize NADPH for lipid biosynthesis via the pentose phosphate pathway (PPP) in the liver and mammary glands [6][7].
HK3 is known to be inhibited by glucose at high concentrations of 1 mmol l−1 (substrate inhibition) but is less sensitive to inhibition by G6P. Interestingly, HK3 responds towards G6P and Pi similarly to HK2, which supports an anabolic role for HK3; further research is needed to answer this question [4][8]. It also has the lowest affinity for the second substrate, ATP, among all HKs, but the physiological role of this property remains elusive [4].
GCK has the highest Km (lowest affinity) for glucose among all canonical HKs (HK1-4), allowing the liver and pancreas to serve as a “glucose buffer” and a “glucose sensor,” respectively. It is not inhibited by G6P and has a 50-fold lower affinity for glucose than other isoforms. Within the liver, the low affinity is tailored to ensure the availability of glucose to physiologically sensitive tissues such as the brain under starvation and its utilization only when glucose is abundantly available. Within the pancreas, this feature allows GCK to act as a “glucose sensor” to regulate insulin release. Mutations in the glucokinase (GCK) gene lead to maturity-onset diabetes of the young, type 2 (MODY-2), and persistent hyperinsulinemic hypoglycemia of infancy (PHHI) [9][10][11]. MODY-2 is a mild type 2 diabetes resulting from a defect in glucose-induced insulin secretion [9][10][12]. Mutations in the GCK leading to MODY-2 are arguably the most common cause of monogenic diabetes due to these specific mutations. More than 40 mutations have been linked to MODY-2, including frameshifts, nonsense, missense, and splice-site variants [1][2][3][13][14][15][16]. The proposed role of GCK as a “glucose sensor” in pancreatic β-cells [5][14][17] is consistent with the MODY-2 phenotype wherein small reductions in β-cell activity increase the threshold for glucose-induced insulin secretion resulting in the phenotype. However, a report by Postic et al. suggests that hepatic GCK also plays a role in MODY-2. Alterations in GCK activity are also associated with many other diseases that have been reviewed elsewhere in detail [17][18]. Owing to its unique role, GCK regulation is complex, and several regulatory mechanisms have been discovered. Alternative and tissue-specific promoters drive GCK transcription and gene expression to varying degrees [19][20][21][22][23][24]. Several metabolites, including insulin, glucose, and hormones, regulate GCK expression at the transcriptional level [25][26][27][28][29]. The regulation of GCK has been recently reviewed elsewhere in more detail [30].
Not much is known about the kinetic and regulatory properties of HKDC1, and it needs further exploration. However, the genetic locus near HKDC1 is a “hot spot” for various “histone modifications,” and it is believed that HKDC1 is subject to different levels of regulation under different physiological and pathophysiological conditions [31][32]. Although HKDC1 has two kinase domains like HK1, there have been contrasting reports on its catalytic potential. An early study suggests that HKDC1 possesses hexokinase activity, where experiments on INS-1 rat pancreatic cells with HKDC1 overexpression showed changes in HK activity [32]. Interestingly, the hexokinase activity of the other HKs was unaffected by the expression of HKDC1 [32]. Going further, the group has recently shown that the hexokinase activity of HKDC1 is quite low, and the principal function of the protein may be more related to binding to mitochondria and modulating glucose flux [33].

2. Roles of Hexokinases in Cancer-Mediated Metabolic Reprogramming

One of the characteristic features of cancer is unabated cell division. For this reason, neoplastic cells preferentially obtain energy and biomolecules through glycolysis through metabolic reprogramming. Metabolic reprogramming refers to the ability of cancer cells to alter their metabolism to support their enhanced metabolic requirements of high ATP and intermediates for biosynthetic processes. This requirement brings about extensive changes in the expression of different hexokinase enzymes.
Hexokinase 1: The expression of HK1 is amplified in some cancers where it is responsible for rewiring the metabolic state towards aerobic glycolysis to supply ATP and macromolecules (Figure 1) [34][35][36]. The observation that most normal cells express HK1 while cancer cells express HK1 and HK2 stimulated interest in reducing HK2 activity in cancers. However, studies have demonstrated that the knockdown of HK2 alone does not inhibit in vivo tumor progression with reduced glucose consumption, suggesting that HK1 compensates for the overall tumorigenic potential. In contrast, the knockdown of HK2 in HK1- HK2+ cancers reduced xenograft tumor progression [37][38][39][40]. These studies suggest a greater involvement of HK1 in tumor progression beyond its currently known role and possibly as a regulatory function in cancer cells. For example, in a study by Daniela et al., HK1 has been shown to be involved in ovarian cancer in a glucose phosphorylation-independent fashion [41]. HK1 also serves as the effector of KRAS4A, an isoform of the most frequently mutated oncogene KRAS, during tumorigenesis [42].
Figure 1. Illustration of the delivery of glucose to membrane-bound HKs in malignant cells. Illustration of the glucose delivery to HKs 1, 2, and HKDC1 bound to the outer mitochondrial membrane (OMM) and metabolic fates of the glucose-6-phosphate (G6P) formed thereof within a malignant cell. Glucose transport across the plasma membrane by glucose transporters is phosphorylated by HKs (HK1, HK2, or HKDC1) bound to a voltage-dependent anion channel (VDAC) located on the outer mitochondrial membrane. VDAC allows direct access of ATP generated by the ATP synthase within the mitochondria to the HKs, which can be transported across the inner-mitochondrial membrane by the adenine nucleotide translocator. To maintain malignant cells’ highly glycolytic metabolic flux, the product G6P is rapidly distributed across key metabolic routes (see thick green arrows). The primary metabolic routes for G6P are either entry into the pentose-phosphate pathway for biosynthesis of nucleic acid precursors or conversion to pyruvate and lactate through glycolysis. In cancer cells, most lactate is transported out of the cells with the aid of lactate transporters. In contrast, small amounts of pyruvate are transported to mitochondria through the pyruvate transporters to supply intermediates to the tricarboxylic acid (TCA) cycle (thin red arrows). Citrate transporters transport citrate produced in the TCA cycle to aid in synthesizing membrane components such as phospholipids and cholesterol, essential for tumor cell proliferation. * Novel hexokinase, HKDC1, with roles still unknown.
Hexokinase 2: HK2 is significantly overexpressed in treatment-resistant primary and metastatic breast cancer [43][44][45][46], bladder cancer [47], cervical squamous cell carcinoma [48], colorectal cancer [49], neuroendocrine tumor [34], ovarian epithelial tumors [35], glioblastoma [36][50], hepatocellular carcinoma [51], laryngeal squamous cell carcinoma [52], lung cancer [53], neuroblastoma [54], pancreatic cancer [55], and prostate cancer. HK2 expression in these cancers inversely correlates to overall patient survival rates [56]. The genetic ablation of HK2 is known to inhibit malignant growth in mouse models [37][38][39][40][57]. A landmark study on an adult tumor model of mice demonstrated the therapeutic effects of systemic deletion of HK2 [57][58][59][60][61]. In addition to its enzymatic activity, the mitochondrial binding ability of HK2 plays a role in inhibiting apoptosis and upregulating synthetic pathways which support tumor growth (Figure 1). The mitochondrial-bound HK2 is therefore elevated in many forms of cancer [43][44][45]. The amplification of HK2 appears to be related to the expression of p53. Recent studies have shown that p53-inducible protein TIGAR (Tp53-induced glycolysis and apoptosis regulator), Akt, and ER stress sensor kinase could regulate mitochondrial HK2 localization [53][60][62][63][64][65][66]. Interestingly, the mitochondrial TIGAR–HK2 complex upregulated HK2 and hypoxia-inducible factor 1 (HIF1) activity, which limits reactive oxygen species (ROS) production and protects against tumor cell death under hypoxic conditions [67][68][69][70][71][72]. It is also observed that the GCK to HK2 switch occurs in hepatocellular carcinoma (HCC), and the expression of HK2 is highest in HCC [70]. Additionally, HK2 is also regulated by epigenetic mediators, including long non-coding RNAs [37][38][44][45], microRNAs [66][67][68][69][70], histone, and DNA methylation [40]. HK2 is localized to the outer mitochondrial membrane through a voltage-dependent anion channel (VDAC) [69] (Figure 1). This association permits direct access to the ATP generated within the mitochondria [67]. This phenomenon is especially significant in malignant cells where rates of aerobic glycolysis go up tremendously to meet the energy demands of the transformed cell (Warburg effect) [36].
Hexokinase 3: HK3 is upregulated in several cancers, including acute myeloid leukemia (AML), where it plays the role of an anti-apoptotic protein to promote tumor cell survival alongside HK1 and 2 [73][74]. The previously identified functions of the enzyme include cell survival through the attenuation of apoptosis and the enhancement of mitochondrial biogenesis [14][75][76]. The latest research about the functions of HK3 in normal and cancer cells has uncovered previously unanticipated roles of this protein. A recent study by Seiler et al. has reported that hexokinase 3 enhances myeloid cell survival via non-glycolytic functions [77]. In contrast, another report by Xu et al. showed that HK3 dysfunction promotes tumorigenesis and immune escape by upregulating macrophage infiltration in renal cell carcinoma [78].
Glucokinase: Glucose phosphorylation activity for GCK has been observed in several cancer cell lines [79]. GCK is also known to interact with BAD (Bcl-2 agonist of cell death) to integrate glycolysis with apoptosis [80][81][82][83]. To date, 17 activating mutations targeted by multiple activators have been identified in the allosteric activator site of GCK [84][85][86][87]. The activating variations and their targeting by the activators lead to enhanced cellular proliferation, including the proliferation of cancer cell lines such as INS, which indicates a putative pro-oncogenic role for GCK [88][89][90]. Although there is no direct evidence for the role of GCK as a pro-oncogene, recent reports exploring somatic variations of allosterically regulated proteins in cancer genomes suggest that somatic mutations of GCK could play a role in tumorigenesis [91]. Těšínský et al. provide the first direct evidence of the role of GCK in tumorigenesis by demonstrating a change in the kinetic properties of GCK which include an increased affinity for glucose and changes in cooperative binding [92].
Hexokinase domain containing 1: Studies performed over the past decade have linked HKDC1 to various functions (Figure 2). Much of the interest in HKDC1’s role in cancer stems from the fact that, like HK1 and 2, it localizes in the mitochondrial outer membrane (MOM) and binds with the voltage-dependent anion channel (VDAC) [93]. Researchers were the first to identify the role of hepatic HKDC1 in glucose metabolism. Using a mouse model of HKDC1, researchers demonstrated that hepatic HKDC1 modulates glucose metabolism and insulin sensitivity in mice. Although HKDC1 has nominal expression in normal hepatocytes [94], it is significantly upregulated in hepatocellular carcinoma (HCC) cells [95][96], implying that it plays an essential role in HCC. By using HKDC1 knockout models, researchers have shown that cellular HK activity is not affected by HKDC1 ablation; however, there is a significant increase in glucose uptake, where the bulk of glucose carbons flow through the glycolytic shunt pathways PPP and HBP (Figure 2) [33]. Researchers further show that HKDC1 interacts with the mitochondria, and its loss results in mitochondrial dysfunction [33]. Since cancer cells require ATP to prepare for cell division during the synthetic (S) phase of the cell cycle, a deficiency in ATP may cause cell cycle arrest. Others have shown that HKDC1 is also significantly increased in breast cancer cells, enhancing glucose uptake and mitochondrial membrane potential to encourage cell survival and growth. In agreement with this phenomenon, HKDC1 knockdown increased the production of reactive oxygen species (ROS), the activation of caspase 3, and apoptosis [97]. Li et al. [98] used RNA-seq data from The Cancer Genome Atlas to pinpoint genetically altered genes in a univariate survival analysis of patients with squamous cell lung carcinoma (SQCLC). Seven thousand two hundred twenty-two genetically modified genes were discovered by the analysis of RNA-seq data from 550 SQCLC patients, and HKDC1 was one of 14 feature genes with more than 100 frequencies linked to a worse prognosis [98][99]. HKDC1 mRNA and protein levels were also expressed higher in lung cancer cell lines than in healthy lung epithelial cells.
Figure 2. Schematic representation of the effects of HKDC1 over-expression in cancer cells. The cell membrane glucose transporters (GLUT 1/3) mediate the glucose uptake, which is degraded to pyruvate by glycolysis. Upregulation of HKDC1 (and other HKs) in many cancer types leads to enhanced generation of glycolytic intermediate, which functions as precursors for numerous metabolic pathways necessary for the biosynthesis of cellular components; pentose phosphate pathway (marked with thick red arrows), cholesterol biosynthesis, and fatty acid biosynthesis. Notably, HKDC1 upregulation leads to an increase in HKDC1-mitochondrial binding, which is responsible for the maintenance of glycolysis and TCA cycle and contributes to unabated cell proliferation through the aversion of apoptosis and endoplasmic reticulum (ER)-mediated stress response mechanisms by reducing the number of physical contact points between ER and mitochondria.
Additionally, there was a direct correlation between the degree of HKDC1 protein expression and histological differentiation, reduced survival, tumor size, pN (N refers to the number of nearby lymph nodes with cancer) stage, and poor prognosis. In agreement with these results, lung cancer cell lines stably overexpressing HKDC1 demonstrated increased glucose consumption, lactate generation, proliferation, migration, and invasion compared to healthy lung epithelial cells [98][99]. A comparison study on RNA sequencing (RNA-Seq) analysis of colorectal cancer (CRC) and matched standard tissue samples has observed significant splicing variations in nine genes in CRC. Interestingly, the authors discovered alternate regulation of the first exon in HKDC1 using exon sequencing (DEXSeq) to uncover variations in relative exon usage. HKDC1 E1a-E3a was elevated in CRC, suggesting a potential functional impact because of a projected change in the HKDC1 protein sequence [100][101][102]. Another study has reported a 13 h phase change in HKDC1 expression between SW480 cells and their metastatic counterpart SW620 (a core clock gene) that occurs in conjunction with a phase shift in aryl hydrocarbon receptor nuclear translocator-like protein-1 (BMAL1). In SW480 cells, silencing BMAL1 results in an elevation of HKDC1 expression, and this effect was eliminated in SW620 cells. These findings imply that HKDC1 and the circadian clock interact, as the circadian clock is altered in metastatic cells [103].
Eukaryotic cells adjust to cellular stress by phosphorylating eukaryotic translation initiation factor 2 alpha (eIF2), which results in the translation of specific transcripts that enable the cell to withstand stress [66][67][68][69][104][105]. Activating transcription factor 4 (ATF4) is a leucine zipper transcription factor that modulates the cellular integrated stress response to allow cells to adapt to and endure stressors [76][106][107]. The overexpression of ATF4 causes the HKDC1 gene transcription to increase significantly under cellular stress, changing hepatocyte mitochondrial dynamics [108]. HKDC1 is upregulated in response to the endoplasmic reticulum (ER) stress or mitochondrial respiratory chain inhibition; however, when these stressors are present in combination with RNA interference to decrease ATF4, HKDC1 gene expression is reduced [108].

References

  1. Wilson, J.E. Isozymes of mammalian hexokinase: Structure, subcellular localization and metabolic function. J. Exp. Biol. 2003, 206 Pt 13, 2049–2057.
  2. Katzen, H.M.; Schimke, R.T. Multiple forms of hexokinase in the rat: Tissue distribution, age dependency, and properties. Proc. Natl. Acad. Sci. USA 1965, 54, 1218–1225.
  3. Sebastian, S.; Hoebee, B.; Hande, M.; Kenkare, U.; Natarajan, A. Assignment of hexokinase types 1, 2, 3 (Hk1, 2, 3) and glucokinase (Gck) to rat chromosome band 20q11, 4q34, 17q12 and 14q21 respectively, by in situ hybridization. Cytogenet. Cell Genet. 1997, 77, 266–267.
  4. Wilson, J.E. Hexokinases. Rev. Physiol. Biochem. Pharmacol. 1995, 126, 65–198.
  5. Cárdenas, M.L.; Cornish-Bowden, A.; Ureta, T. Evolution and regulatory role of the hexokinases. Biochim. Biophys. Acta Mol. Cell Res. 1998, 1401, 242–264.
  6. Sebastian, S.; Horton, J.D.; Wilson, J.E. Anabolic function of the Type II isozyme of hexokinase in hepatic lipid synthesis. Biochem. Biophys. Res. Commun. 2000, 270, 886–891.
  7. Kaselonis, G.L.; McCabe, E.R.; Gray, S.M. Expression of hexokinase 1 and hexokinase 2 in mammary tissue of nonlactating and lactating rats: Evaluation by RT-PCR. Mol. Genet. Metab. 1999, 68, 371–374.
  8. Kawai, S. Hypothesis: Structures, evolution, and ancestor of glucose kinases in the hexokinase family. J. Biosci. Bioeng. 2005, 99, 320–330.
  9. Velho, G.; Froguel, P.; Clement, K.; Pueyo, M.E.; Rakotoambinina, B.; Zouali, H.; Passa, P.; Cohen, D.; Robert, J.J. Primary pancreatic beta-cell secretory defect caused by mutations in glucokinase gene in kindreds of maturity onset diabetes of the young. Lancet 1992, 340, 444–448.
  10. Velho, G.; Petersen, K.F.; Perseghin, G.; Hwang, J.H.; Rothman, D.L.; Pueyo, M.E.; Cline, G.W.; Froguel, P.; Shulman, G.I. Impaired hepatic glycogen synthesis in glucokinase-deficient (MODY-2) subjects. J. Clin. Investig. 1996, 98, 1755–1761.
  11. Osbak, K.K.; Colclough, K.; Saint-Martin, C.; Beer, N.L.; Bellanné-Chantelot, C.; Ellard, S.; Gloyn, A.L. Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Hum. Mutat. 2009, 30, 1512–1526.
  12. Byrne, M.M.; Sturis, J.; Clement, K.; Vionnet, N.; Pueyo, M.E.; Stoffel, M.; Takeda, J.; Passa, P.; Cohen, D.; Bell, G.I.; et al. Insulin secretory abnormalities in subjects with hyperglycemia due to glucokinase mutations. J. Clin. Investig. 1994, 93, 1120–1130.
  13. Warburg, O. On the origin of cancer cells. Science 1956, 123, 309–314.
  14. Liberti, M.V.; Locasale, J.W. The Warburg effect: How does it benefit cancer cells? Trends Biochem. Sci. 2016, 41, 211–218.
  15. Matschinsky, F.M.; Wilson, D.F. The central role of glucokinase in glucose homeostasis: A perspective 50 years after demonstrating the presence of the enzyme in islets of Langerhans. Front. Physiol. 2019, 10, 148.
  16. Martínez-Reyes, I.; Chandel, N.S. Cancer metabolism: Looking forward. Nat. Rev. Cancer 2021, 21, 669–680.
  17. Postic, C.; Shiota, M.; Magnuson, M.A. Cell-specific roles of glucokinase in glucose homeostasis. Recent Prog. Hormone Res. 2001, 56, 195–217.
  18. Franz, M.M. Glucokinase, glucose homeostasis, and diabetes mellitus. Curr. Diab. Rep. 2005, 5, 171–176.
  19. Iynedjian, P.B. Molecular physiology of mammalian glucokinase. Cell Mol. Life Sci. 2009, 66, 27–42.
  20. Moates, J.M.; Nanda, S.; Cissell, M.A.; Tsai, M.-J.; Stein, R. BETA2 activates transcription from the upstream glucokinase gene promoter in islet β-cells and gut endocrine cells. Diabetes 2003, 52, 403–408.
  21. Jetton, T.L.; Liang, Y.; Pettepher, C.C.; Zimmerman, E.C.; Cox, F.G.; Horvath, K.; Matschinsky, F.M.; Magnuson, M.A. Analysis of up-stream glucokinase promoter activity in transgenic mice and identification of glucokinase in rare neuroendocrine cells in the brain and gut. J. Biol. Chem. 1994, 269, 3641–3654.
  22. Moates, J.M.; Magnuson, M.A. The Pal elements in the upstream glucokinase promoter exhibit dyad symmetry and display cell-specific enhancer activity when multimerized. Diabetologia 2004, 47, 1632–1640.
  23. Sternisha, S.M.; Miller, B.G. Molecular and Cellular Regulation of Human Glucokinase. Arch. Biochem. Biophys.
  24. Peter, A.; Stefan, N.; Cegan, A.; Walenta, M.; Wagner, S.; Königsrainer, A.; Königsrain-er, A.; Machicao, F.; Schick, F.; Häring, H.-U.; et al. Hepatic Glucokinase Expression Is Associated with Lipogenesis and Fatty Liver in Humans. J. Clin. Endocrinol. Metab. 2011, 96, E1126–E1130.
  25. Iynedjian, P.B. Mammalian glucokinase and its gene. Biochem. J. 1993, 293 Pt 1, 1–13.
  26. Iynedjian, P.B.; Gjinovci, A.; Renold, A.E. Stimulation by insulin of glucokinase gene transcription in liver of diabetic rats. J. Biol. Chem. 1988, 263, 740–744.
  27. Wu, C.; Okar, D.A.; Stoeckman, A.K.; Peng, L.J.; Herrera, A.H.; Herrera, J.E.; Towle, H.C.; Lange, A.J. A potential role for fructose-2,6-bisphosphate in the stimulation of hepatic glucokinase gene expression. Endocrinology 2004, 145, 650–658.
  28. Roth, U.; Curth, K.; Unterman, T.G.; Kietzmann, T. The transcription factors HIF-1 and HNF-4 and the coactivator p300 are involved in insulin-regulated glucokinase gene expression via the phosphatidylinositol 3-kinase/protein kinase B pathway. J. Biol. Chem. 2004, 279, 2623–2631.
  29. Iynedjian, P.B.; Marie, S.; Gjinovci, A.; Genin, B.; Deng, S.P.; Buhler, L.; Morel, P.; Mentha, G. Glucokinase and cytosolic phosphoenolpyruvate carboxykinase (GTP) in the human liver. Regulation of gene expression in cultured hepatocytes. J. Clin. Investig. 1995, 95, 1966–1973.
  30. Agius, L. Hormonal and Metabolite Regulation of Hepatic Glucokinase. Annu. Rev. Nutr. 2016, 36, 389–415.
  31. Zapater, J.L.; Lednovich, K.R.; Khan, M.W.; Pusec, C.M.; Layden, B.T. Hexokinase domain-containing protein-1 in metabolic diseases and beyond. Trends Endocrinol. Metab. 2022, 33, 72–84.
  32. Guo, C.; Ludvik, A.E.; Arlotto, M.E.; Hayes, M.G.; Armstrong, L.L.; Scholtens, D.M. Coordinated regulatory variation associated with gestational hyperglycemia regulates expression of the novel hexokinase HKDC1. Nat. Commun. 2015, 6, 6069.
  33. Khan, M.W.; Terry, A.R.; Priyadarshini, M.; Ilievski, V.; Farooq, Z.; Guzman, G.; Cordoba-Chacon, J.; Ben-Sahra, I.; Wicksteed, B.; Layden, B.T. The hexokinase “HKDC1” interaction with the mitochondria is essential for liver cancer progression. Cell Death Dis. 2022, 28, 660.
  34. Labrecque, M.P.; Brown, L.G.; Coleman, I.M.; Nguyen, H.M.; Lin, D.W.; Corey, E.; Nelson, P.S.; Morrissey, C. Cabozantinib can block growth of neuroendocrine prostate cancer patient-derived xenografts by disrupting tumor vasculature. PLoS ONE 2021, 16, e0245602.
  35. Lee, H.G.; Kim, H.; Son, T.; Jeong, Y.; Kim, S.U.; Dong, S.M.; Park, Y.N.; Lee, J.D.; Lee, J.M.; Park, J.H. Regulation of HK2 expression through alterations in CpG methylation of the HK2 promoter during progression of hepatocellular carcinoma. Oncotarget 2016, 7, 41798–41810.
  36. Sun, L.; Shukair, S.; Naik, T.J.; Moazed, F.; Ardehali, H. Glucose phosphorylation and mitochondrial binding are required for the protective effects of hexokinases I and, II. Mol. Cell Biol. 2008, 28, 1007–1017.
  37. Wilson, J.E. Regulation of mammalian hexokinase activity. In Regulation of Carbohydrate Metabolism; Beitner, R., Ed.; CRC: Boca Raton, FL, USA, 1985; pp. 45–85.
  38. Li, Y.; Tian, H.; Luo, H.; Fu, J.; Jiao, Y.; Li, Y. Prognostic significance and related mechanisms of hexokinase 1 in ovarian cancer. Onco Targets Ther. 2020, 13, 11583–11594.
  39. Xu, S.; Catapang, A.; Doh, H.M.; Bayley, N.A.; Lee, J.T.; Braas, D.; Graeber, T.G.; Herschman, H.R. Hexokinase 2 is targetable for HK1 negative, HK2 positive tumors from a wide variety of tissues of origin. J. Nucl. Med. 2019, 60, 212–217.
  40. Xu, S.; Catapang, A.; Braas, D.; Stiles, L.; Doh, H.M.; Lee, J.T.; Graeber, T.G.; Damoiseaux, R.; Shirihai, O.; Herschman, H.R. A precision therapeutic strategy for hexokinase 1-null, hexokinase 2-positive cancers. Cancer Metab. 2018, 6, 7.
  41. Šimčíková, D.; Gardáš, D.; Hložková, K.; Hruda, M.; Žáček, P.; Rob, L.; Heneberg, P. Loss of hexokinase 1 sensitizes ovarian cancer to high-dose metformin. Cancer Metab. 2021, 9, 41.
  42. Amendola, C.R.; Mahaffey, J.P.; Parker, S.J.; Ahearn, I.M.; Chen, W.C.; Zhou, M.; Court, H.; Shi, J.; Mendoza, S.L.; Morten, M.J.; et al. KRAS4 directly regulates HK1. Nature 2019, 576, 482–486.
  43. Bacci, M.; Giannoni, E.; Fearns, A.; Ribas, R.; Gao, Q.; Taddei, M.L.; Pintus, G.; Dowsett, M.; Isacke, C.M.; Martin, L.A. miR-155 drives metabolic reprogramming of ER+ breast cancer cells following long-term estrogen deprivation and predicts clinical response to aromatase inhibitors. Cancer Res. 2016, 76, 1615–1626.
  44. van ‘t Veer, L.J.; Dai, H.; van de Vijver, M.J.; He, Y.D.; Hart, A.A.M.; Mao, M.; Peterse, H.L.; van der Kooy, K.; Marton, M.J.; Witteveen, A.T.; et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002, 415, 530–536.
  45. Liu, X.; Miao, W.; Huang, M.; Li, L.; Dai, X.; Wang, Y. Elevated hexokinase II expression confers acquired resistance to 4-hydroxytamoxifen in breast cancer cells. Mol. Cell Proteomics 2019, 18, 2273–2284.
  46. Palmieri, D.; Fitzgerald, D.; Shreeve, S.M.; Hua, E.; Bronder, J.L.; Weil, R.J.; Davis, S.; Stark, A.M.; Merino, M.J.; Kurek, R.; et al. Analyses of resected human brain metastases of breast cancer reveal the association between up-regulation of hexokinase 2 and poor prognosis. Mol. Cancer Res. 2009, 7, 1438–1445.
  47. Yang, X.; Cheng, Y.; Li, P.; Tao, J.; Deng, X.; Zhang, X.; Gu, M.; Lu, Q.; Yin, C. A lentiviral sponge for miRNA-21 diminishes aerobic glycolysis in bladder cancer T24 cells via the PTEN/PI3K/AKT/mTOR axis. Tumour Biol. 2015, 36, 383–391.
  48. Huang, X.; Liu, M.; Sun, H.; Wang, F.; Xie, X.; Chen, X.; Su, J.; He, Y.; Dai, Y.; Wu, H.; et al. HK2 is a radiation resistant and independent negative prognostic factor for patients with locally advanced cervical squamous cell carcinoma. Int. J. Clin. Exp. Pathol. 2015, 8, 4054–4063.
  49. Iwamoto, M.; Kawada, K.; Nakamoto, Y.; Itatani, Y.; Inamoto, S.; Toda, K.; Kimura, H.; Sasazuki, T.; Shirasawa, S.; Okuyama, H.; et al. Regulation of ^18F-FDG accumulation in colorectal cancer cells with mutated KRAS. J. Nucl. Med. 2014, 55, 2038–2044.
  50. Demetrius, L.; Tuszynski, J.A. Quantum metabolism explains the allometric scaling of metabolic rates. J. R. Soc. Interface 2010, 7, 507–514.
  51. Kwee, S.A.; Hernandez, B.; Chan, O.; Wong, L. Choline kinase alpha and hexokinase-2 protein expression in hepatocellular carcinoma: Association with survival. PLoS ONE 2012, 7, e46591.
  52. Chen, J.; Zhang, S.; Li, Y.; Tang, Z.; Kong, W. Hexokinase 2 overexpression promotes the proliferation and survival of laryngeal squamous cell carcinoma. Tumor Biol. 2014, 35, 3743–3753.
  53. Wang, H.; Wang, L.; Zhang, Y.; Wang, J.; Deng, Y.; Lin, D. Inhibition of glycolytic enzyme hexokinase II (HK2) suppresses lung tumor growth. Cancer Cell Int. 2016, 16, 38.
  54. Botzer, L.E.; Maman, S.; Sagi-Assif, O.; Meshel, T.; Nevo, I.; Yron, I.; Witz, I.P. Hexokinase 2 is a determinant of neuroblastoma metastasis. Br. J. Cancer 2016, 114, 759–766.
  55. Ogawa, H.; Nagano, H.; Konno, M.; Eguchi, H.; Koseki, J.; Kawamoto, K.; Nishida, N.; Colvin, H.; Tomokuni, A.; Tomimaru, Y.; et al. The combination of the expression of hexokinase 2 and pyruvate kinase M2 is a prognostic marker in patients with pancreatic cancer. Mol. Clin. Oncol. 2015, 3, 563–571.
  56. He, H.C.; Bi, X.C.; Zheng, Z.W.; Dai, Q.S.; Han, Z.D.; Liang, Y.X.; Ye, Y.K.; Zeng, G.H.; Zhu, G.; Zhong, W.D. Real-time quantitative RT-PCR assessment of PIM-1 and hK2 mRNA expression in benign prostate hyperplasia and prostate cancer. Med. Oncol. 2009, 26, 303–308.
  57. Patra, K.C.; Wang, Q.; Bhaskar, P.T.; Miller, L.; Wang, Z.; Wheaton, W.; Chandel, N.; Laakso, M.; Muller, W.J.; Allen, E.L. Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell 2013, 24, 213–228.
  58. Christofk, H.R.; Vander Heiden, M.G.; Harris, M.H.; Ramanathan, A.; Gerszten, R.E.; Wei, R.; Fleming, M.D.; Schreiber, S.L.; Cantley, L.C. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 2008, 452, 230–233.
  59. Marybeth, A.; Raoud, M.; Richard, M.; Jen, J.Y. Hexokinase 2 promotes tumor growth and metastasis by regulating lactate production in pancreatic cancer. Oncotarget 2016, 8, 56081–56094.
  60. Wang, L.; Xiong, H.; Wu, F.; Zhang, Y.; Wang, J.; Zhao, L.; Guo, X.; Chang, L.J.; Zhang, Y.; You, M.J.; et al. Hexokinase 2-mediated Warburg effect is required for PTEN- and p53-deficiency-driven prostate cancer growth. Cell Rep. 2014, 8, 1461–1474.
  61. Wolf, A.; Agnihotri, S.; Micallef, J.; Mukherjee, J.; Sabha, N.; Cairns, R.; Hawkins, C.; Guha, A. Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme. J. Exp. Med. 2011, 208, 313–326.
  62. Semenza, G.L. HIF-1: Upstream and downstream of cancer metabolism. Curr. Opin. Genet. Dev. 2010, 20, 51–56.
  63. Cheung, E.C.; Ludwig, R.L.; Vousden, K.H. Mitochondrial localization of TIGAR under hypoxia stimulates HK2 and lowers ROS and cell death. Proc. Natl. Acad. Sci. USA 2012, 109, 20491–20496.
  64. Neary, C.L.; Pastorino, J.G. Akt inhibition promotes hexokinase 2 redistribution and glucose uptake in cancer cells. J. Cell Physiol. 2013, 228, 1943–1948.
  65. Gao, F.; Li, M.; Liu, W.B.; Zhou, Z.S.; Zhang, R.; Li, J.L.; Zhou, K.C. Epigallocatechin gallate inhibits human tongue carcinoma cells via HK2-mediated glycolysis. Oncol. Rep. 2015, 33, 1533–1539.
  66. Hou, X.; Liu, Y.; Liu, H.; Chen, X.; Liu, M.; Che, H.; Guo, F.; Wang, C.; Zhang, D.; Wu, J.; et al. PERK silence inhibits glioma cell growth under low glucose stress by blockage of p-AKT and subsequent HK2’s mitochondria translocation. Sci. Rep. 2015, 5, 9065.
  67. Yoshino, H.; Enokida, H.; Itesako, T.; Kojima, S.; Kinoshita, T.; Tatarano, S.; Chiyomaru, T.; Nakagawa, M.; Seki, N. Tumor-suppressive microRNA-143/145 cluster targets hexokinase-2 in renal cell carcinoma. Cancer Sci. 2013, 104, 1567–1574.
  68. Guo, W.; Qiu, Z.; Wang, Z.; Wang, Q.; Tan, N.; Chen, T.; Chen, Z.; Huang, S.; Gu, J.; Li, J.; et al. MiR-199a-5p is negatively associated with malignancies and regulates glycolysis and lactate production by targeting hexokinase 2 in liver cancer. Hepatology 2015, 62, 1132–1144.
  69. Qin, Y.; Cheng, C.; Lu, H.; Wang, Y. miR-4458 suppresses glycolysis and lactate production by directly targeting hexokinase2 in colon cancer cells. Biochem. Biophys. Res. Commun. 2016, 469, 37–43.
  70. Jiang, S.; Zhang, L.F.; Zhang, H.W.; Hu, S.; Lu, M.H.; Liang, S.; Li, B.; Li, Y.; Li, D.; Wang, E.D.; et al. A novel miR-155/miR-143 cascade controls glycolysis by regulating hexokinase 2 in breast cancer cells. EMBO J. 2012, 31, 1985–1998.
  71. Gregersen, L.H.; Jacobsen, A.; Frankel, L.B.; Wen, J.; Krogh, A.; Lund, A.H. MicroRNA-143 down-regulates Hexokinase 2 in colon cancer cells. BMC Cancer 2012, 12, 232.
  72. Dai, W.; Wang, F.; Lu, J.; Xia, Y.; He, L.; Chen, K.; Li, J.; Li, S.; Liu, T.; Zheng, Y.; et al. By reducing hexokinase 2, resveratrol induces apoptosis in HCC cells addicted to aerobic glycolysis and inhibits tumor growth in mice. Oncotarget 2015, 6, 13703–13717.
  73. Federzoni, E.A.; Valk, P.J.; Torbett, B.E.; Haferlach, T.; Löwenberg, B.; Fey, M.F.; Tschan, M.P. PU.1 is linking the glycolytic enzyme HK3 in neutrophil differentiation and survival of APL cells. Blood 2012, 119, 4963–4970.
  74. Hai-Yan, G.; Xin-Guo, L.; Xi, C.; Jing-Hua, W. Identification of key genes affecting disease free survival time of pediatric acute lymphoblastic leukemia based on bioinformatic analysis. Blood Cells Mol. Dis. 2015, 54, 38–43.
  75. Lu, J. The Warburg metabolism fuels tumor metastasis. Cancer Metastasis Rev. 2019, 38, 157–164.
  76. Jose, C.; Bellance, N.; Rossignol, R. Choosing between glycolysis and oxidative phosphorylation: A tumor’s dilemma? Biochim. Biophys. Acta 2011, 1807, 552–561.
  77. Seiler, K.; Humbert, M.; Minder, P.; Mashimo, I.; Schläfli, A.M.; Krauer, D.; Federzoni, E.A.; Vu, B.; Moresco, J.J.; Yates, J.R., 3rd; et al. Hexokinase 3 enhances myeloid cell survival via non-glycolytic functions. Cell Death Dis. 2022, 13, 448.
  78. Xu, W.; Liu, W.R.; Xu, Y.; Tian, X.; Anwaier, A.; Su, J.Q.; Zhu, W.K.; Shi, G.H.; Wei, G.M. Hexokinase 3 dysfunction promotes tumorigenesis and immune escape by upregulating monocyte/macrophage infiltration into the clear cell renal cell carcinoma microenvironment. Int. J. Biol. Sci. 2021, 17, 2205–2222.
  79. Board, M.; Colquhoun, A.; Newsholme, E.A. High Km glucose-phosphorylating (glucokinase) activities in a range of tumor cell lines and inhibition of rates of tumor growth by the specific enzyme inhibitor mannoheptulose. Cancer Res. 1995, 55, 3278–3285.
  80. Danial, N.N.; Gramm, C.F.; Scorrano, L.; Zhang, C.Y.; Krauss, S.; Ranger, A.M.; Datta, S.R.; Greenberg, M.E.; Licklider, L.J.; Lowell, B.B.; et al. BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature 2003, 424, 952–956.
  81. Bui, N.L.C.; Pandey, V.; Zhu, T.; Ma, L.; Basappa, L.P.E. Bad phosphorylation as a target of inhibition in oncology. Cancer Lett. 2018, 415, 17–26.
  82. Danial, N.N. BAD: Undertaker by night, candyman by day. Oncogene 2008, 27 (Suppl. 1), S53–S70.
  83. Jiang, P.; Du, W.; Heese, K.; Wu, M. The Bad guy cooperates with good cop p53: Bad is transcriptionally up-regulated by p53 and forms a Bad/p53 complex at the mitochondria to induce apoptosis. Mol. Cell Biol. 2006, 26, 9071–9082.
  84. Matschinsky, F.M.; Magnuson, M.A.; Zelent, D.; Jetton, T.L.; Doliba, N.; Han, Y.; Taub, R.; Grimsby, J. The network of glucokinase-expressing cells in glucose homeostasis and the potential of glucokinase activators for diabetes therapy. Diabetes 2006, 55, 1–12.
  85. Joseph, G.; Ramakanth, S.; Wendy, L.C.; Nancy-Ellen, H.; Fred, T.B.; John, W.C.; Kevin, R.G.; Darryl, H.; Robert, K. Allosteric Activators of Glucokinase: Potential Role in Diabetes Therapy. Science 2003, 301, 370–373.
  86. Matschinsky, F.M. Assessing the potential of glucokinase activators in diabetes therapy. Nat. Rev. Drug Discov. 2009, 8, 399–416.
  87. Akinobu N and Yasuo, T. Present status of clinical deployment of glucokinase activators. J. Diabetes Investig. 2015, 6, 124–132.
  88. Yoon, S.O.; Youn-Jung, L.; Kaapjoo, P.; Hyun Ho, C.; Sangjong, Y.; Hee-Sook, J. Treatment with glucokinase activator, YH-GKA, increases cell proliferation and decreases glucotoxic apoptosis in INS-1 cells. Eur. J. Pharm. Sci. 2014, 51, 137–145.
  89. Porat, S.; Weinberg-Corem, N.; Tornovsky-Babaey, S.; Schyr-Ben-Haroush, R.; Hija, A.; Stolovich-Rain, M.; Dadon, D.; Granot, Z.; Ben-Hur, V.; White, P.; et al. Control of pancreatic β cell regeneration by glucose metabolism. Cell Metab. 2011, 13, 440–449.
  90. Kassem, S.; Bhandari, S.; Rodríguez-Bada, P.; Motaghedi, R.; Heyman, M.; García-Gimeno, M.A.; Cobo-Vuilleumier, N.; Sanz, P.; Maclaren, N.K.; Rahier, J.; et al. Large islets, beta-cell proliferation, and a glucokinase mutation. N. Engl. J. Med. 2010, 362, 1348–1350.
  91. Shen, Q.; Cheng, F.; Song, H.; Lu, W.; Zhao, J.; An, X.; Liu, M.; Chen, G.; Zhao, Z.; Zhang, J. Proteome-Scale Investigation of Protein Allosteric Regulation Perturbed by Somatic Mutations in 7,000 Cancer Genomes. Am. J. Hum. Genet. 2017, 100, 5–20.
  92. Těšínský, M.; Šimčíková, D.; Heneberg, P. First evidence of changes in enzyme kinetics and stability of glucokinase affected by somatic cancer-associated variations. Biochim. Biophys. Acta Proteins Proteom. 2019, 1867, 213–218.
  93. Pusec, C.M.; De Jesus, A.; Khan, M.W.; Terry, A.R.; Ludvik, A.E.; Xu, K.; Giancola, N.; Pervaiz, H.; Smith, E.D.; Ding, X.; et al. Hepatic HKDC1 expression contributes to liver metabolism. Endocrinology 2019, 160, 313–330.
  94. Khan, M.W.; Ding, X.; Cotler, S.J.; Clarke, M.; Layden, B.T. Studies on the tissue localization of HKDC1, a putative novel fifth hexokinase, in humans. J. Histochem. Cytochem. 2018, 66, 385–392.
  95. Orci, L.A.; Sanduzzi-Zamparelli, M.; Caballol, B.; Sapena, V.; Colucci, N.; Torres, F.; Bruix, J.; Reig, M.; Toso, C. Incidence of hepatocellular carcinoma in patients with nonalcoholic fatty liver disease: A systematic review, meta-analysis, and meta-regression. Clin. Gastroenterol. Hepatol. 2021, 20, 283–292.e10.
  96. Nagaoki, Y.; Hyogo, H.; Ando, Y.; Kosaka, Y.; Uchikawa, S.; Nishida, Y.; Teraoka, Y.; Morio, K.; Fujino, H. Increasing incidence of non-HBV- and non-HCV-related hepatocellular carcinoma: Single-institution 20-year study. BMC Gastroenterol. 2021, 21, 306.
  97. Chen, X.; Lv, Y.; Sun, Y.; Zhang, H.; Xie, W.; Zhong, L.; Chen, Q.; Li, M.; Li, L.; Feng, J.; et al. PGC1β regulates breast tumor growth and metastasis by SREBP1-mediated HKDC1 expression. Front. Oncol. 2019, 9, 290.
  98. Li, J.; Wang, J.; Chen, Y.; Yang, L.; Chen, S. A prognostic 4-gene expression signature for squamous cell lung carcinoma. J. Cell. Physiol. 2017, 232, 3702–3713.
  99. Yixiang, Z.; Puyuan, X.; Junling, L. Treatment of advanced squamous cell lung cancer. Chin. J. Lung Cancer 2016, 19, 687–691.
  100. Jia, H.; Wang, A.; Lian, H.; Shen, Y.; Wang, Q.; Zhou, Z.; Zhang, R.; Li, K.; Liu, C. Identification of novel alternative splicing isoform biomarkers and their association with overall survival in colorectal cancer. BMC Gastroenterol. 2020, 20, 1–12.
  101. Majem, M.; Juan, O.; Insa, A.; Reguart, N.; Trigo, J.M.; Carcereny, E.; García-Campelo, R.; García, Y.; Guirado, M.; Provencio, M. SEOM clinical guidelines for the treatment of non-small cell lung cancer (2018). Clin Transl Oncol. 2019, 21, 3–17.
  102. Anders, S.; Reyes, A.; Huber, W. Detecting differential usage of exons from RNA-seq data. Genome Res. 2012, 22, 2008–2017.
  103. Fuhr, L.; El-Athman, R.; Scrima, R.; Cela, O.; Carbone, A.; Knoop, H.; Li, Y.; Hoffmann, K.; Laukkanen, M.O.; Corcione, F.; et al. The Circadian Clock Regulates Metabolic Phenotype Rewiring Via HKDC1 and Modulates Tumor Progression and Drug Response in Colorectal Cancer. EBioMedicine 2018, 33, 105–121.
  104. Fan, L.; Huang, C.; Li, J.; Gao, T.; Lin, Z.; Yao, T. Long non-coding RNA urothelial cancer associated 1 regulates radioresistance via the hexokinase 2/glycolytic pathway in cervical cancer. Int. J. Mol. Med. 2018, 42, 2247–2259.
  105. Ma, Y.; Hu, M.; Zhou, L.; Ling, S.; Li, Y.; Kong, B.; Huang, P. Long non-coding RNA HOTAIR promotes cancer cell energy metabolism in pancreatic adenocarcinoma by upregulating hexokinase-2. Oncol. Lett. 2019, 18, 2212–2219.
  106. Nabi, K.; Le, A. The Intratumoral Heterogeneity of Cancer Metabolism. Adv. Exp. Med. Biol. 2021, 1311, 149–160.
  107. Antonio, M.J.; Zhang, C.; Le, A. Different Tumor Microenvironments Lead to Different Metabolic Phenotypes. Adv. Exp. Med. Biol. 2021, 1311, 137–147.
  108. Evstafieva, A.G.; Kovaleva, I.E.; Shoshinova, M.S.; Budanov, A.V.; Chumakov, P.M. Implication of KRT16, FAM129A and HKDC1 genes as ATF4 regulated components of the integrated stress response. PLoS ONE 2018, 13, e0191107.
More
Information
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : , , , ,
View Times: 574
Revisions: 3 times (View History)
Update Date: 14 Apr 2023
1000/1000
Video Production Service