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Targeting Fbpase Is an Emerging Novel Approach for Cancer Therapy Gao‑Min Liu and Yao‑Ming Zhang*

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Targeting Fbpase Is an Emerging Novel Approach for Cancer Therapy Gao‑Min Liu and Yao‑Ming Zhang* Liu and Zhang Cancer Cell Int (2018) 18:36 https://doi.org/10.1186/s12935-018-0533-z Cancer Cell International REVIEW Open Access Targeting FBPase is an emerging novel approach for cancer therapy Gao‑Min Liu and Yao‑Ming Zhang* Abstract Cancer is a leading cause of death in both developed and developing countries. Metabolic reprogramming is an emerging hallmark of cancer. Glucose homeostasis is reciprocally controlled by the catabolic glycolysis and anabolic gluconeogenesis pathways. Previous studies have mainly focused on catabolic glycolysis, but recently, FBPase, a rate- limiting enzyme in gluconeogenesis, was found to play critical roles in tumour initiation and progression in several cancer types. Here, we review recent ideas and discoveries that illustrate the clinical signifcance of FBPase expression in various cancers, the mechanism through which FBPase infuences cancer, and the mechanism of FBPase silencing. Furthermore, we summarize some of the drugs targeting FBPase and discuss their potential use in clinical applications and the problems that remain unsolved. Keywords: FBPase, Cancer, Clinical signifcance, Mechanism Background [8, 9]. Aerobic glycolysis leads to several advantages for Cancer is one of the leading causes of death worldwide tumour growth by increasing glucose intake, enhancing [1]. In the past decade, reprogramming of energy metab- lactate production and secretion, and diverting glycolytic olism has emerged as new hallmarks of cancer [2]. Tere intermediates to anabolic reactions such as ribose syn- is increasing epidemiological evidence that links the risk thesis, serine and glycine synthesis, phosphoglycerol syn- of cancer with metabolic disorders, such as diabetes and thesis, and protein glycosylation [10]. Moreover, recent obesity [3]. However, the complete regulatory network of studies have developed promising individualized thera- metabolism reprogramming remains to be elucidated. peutic strategies by targeting the altered energy metabo- Glucose homeostasis is reciprocally controlled by the lism for the treatment of cancer [11]. catabolic glycolysis and anabolic gluconeogenesis path- Tough our understanding of metabolic reprogram- ways. Under normoxic conditions, normal cells process ming in cancer is progressing at an unprecedented glucose frst to pyruvate via glycolysis in the cytosol and pace, previous studies have mainly focused on glyco- thereafter to carbon dioxide in the mitochondria (oxida- lysis. Recently, fructose-1,6-bisphosphatase (FBPase), a tive phosphorylation, OXPHOS); under anaerobic condi- rate-limiting enzyme responsible for gluconeogenesis, tions, glycolysis is favoured, and relatively little pyruvate was found to play critical roles in tumour initiation and is dispatched to the oxygen-consuming mitochondria [4, progression in several cancer types [12–28]. Here, we 5]. However, as frst observed by Otto Warburg in the search Pubmed, EMbase, Web of Science using keywords 1920s, some cancer cells preferentially rely on glycolysis, “FBPase” and “cancer” (the most recent published report even in conditions of high oxygen tension (‘‘aerobic gly- search date: 1 August 2017) and review recent ideas and colysis” or “the Warburg efect’’) [6, 7]. Aerobic glycolysis discoveries regarding the role of FBPase in cancer. was validated with the wide use of 18F-deoxyglucose posi- tron emission tomography (FDG-PET) in most cancers FBPase location and regulation FBPase (EC 3.1.3.11), which catalyses the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate and *Correspondence: [email protected] inorganic phosphate, is a rate-limiting enzyme responsi- Department of Hepatobiliary Surgery, Meizhou People’s Hospital, No. 38 Huangtang Road, Meizhou 514000, China ble for gluconeogenesis and glyconeogenesis and, more © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Liu and Zhang Cancer Cell Int (2018) 18:36 Page 2 of 16 generally, for the control of energy metabolism and glu- and kidneys, is located at chromosome region 9q22.3. cose homeostasis [29]. In mammals, two separate genes, FBP1 consists of seven exons which span more than FBP1 and FBP2, encode the liver and muscle isoforms 31 kb that encode 338 amino acids and six introns [30]. of FBPase, respectively. Te FBP1 gene, which is mainly Te FBP1 promoter has been well characterized since expressed in gluconeogenic organs, such as the liver 2000 [31]. Te FBP2 gene, which was initially isolated Fig. 1 Amino acid sequences and characteristic homotetrameric structure of human FBPase. This fgure provides the human FBP1 and FBP2 amino acid sequence. Human FBP2 is 77% identical to human FBP2 [34]. The sequence alignments were run through BLAST. The characteristic homotetra‑ meric structure of human FBPase was shown [35] Liu and Zhang Cancer Cell Int (2018) 18:36 Page 3 of 16 from muscle tissues and later found to be expressed in FBPase-2, leading to the dephosphorylation of F2,6BP all cells, is located at chromosome region 1p36.1 [32]. and concomitant increases in FBPase activity and glu- FBP2 encodes a 339-amino acid protein that shares 77% coneogenesis [45]. In addition, PKA activates cAMP identity with the FBP1 protein [33]. However, the pro- response element-binding protein (CREB), the CREB moter of the FBP2 gene has not yet been characterized. coactivator CRTC2 [52], and the class II histone deacety- All FBPases are homotetrameric proteins with a molecu- lases (HDACs)/FOXO pathways [53, 54] and promotes lar weight of approximately 37 kDa per subunit (Fig. 1). the expression of key gluconeogenic genes; however, it FBP1 has been identifed as the regulatory enzyme of suppresses the expression of glycolytic genes. Gluco- gluconeogenesis, but the physiological role of FBP2 is far corticoid hormones and glucagon plays essential syn- from clear. ergistic roles in the regulation of gluconeogenesis [55]. Acute regulation of FBPase is achieved mainly through Te response to glucocorticoids is mediated by the glu- its oscillation between two conformational states: the cocorticoid receptor (GR), which binds to glucocorti- inactive T form when in complex with AMP and the coid responsive elements (GREs) in the promoters of active R form [29, 36–40]. By modulating pyruvate kinase gluconeogenic genes [56]. In contrast, insulin acts to activity, fructose-1,6-bisphosphate (F1,6BP) afects repress the transcription of gluconeogenic enzymes. Tis substrate cycling in the pyruvatel/phosphoenolpyru- repression of the expression of gluconeogenic enzymes vate (PEP) substrate cycle [41]. Phosphofructokinase-1 is achieved via the activation of the insulin-phosphoi- (PFK1), the “gatekeeper” of glycolysis, converts fructose- nositide 3-kinase (PI3K)-Akt pathway or suppression of 6-phosphate (F6P) to F1,6BP and has the opposite efect the cAMP/PKA/CREB pathway [57] (Fig. 2). of FBPase in regulating F1,6BP [42]. Fructose-2,6-bi- sphosphate (F2,6BP) is a potent allosteric activator of FBPase and non‑cancerous diseases PFK1 and a competitive inhibitor of FBPase [5, 41–44]. FBP1 defciency When the level of F2,6BP is low, the rates of gluconeo- Mutations in the FBP1 gene cause FBP1 defciency, an genesis are high (such as in starvation and diabetes). inherited autosomal recessive disorder, which leads to Conversely, when the level of F2,6BP is high, the rate of the impairment of glucose synthesis from all gluconeo- gluconeogenesis is low (such as during refeeding and genic precursors [58]. Tis defciency was frst described insulin administration) [5]. Te synthesis and hydrolysis by Baker and Winegrad in 1970 [59]. Tis disorder is of this regulator are catalysed by the bifunctional enzyme characterized by recurrent episodes of hypoglycaemia 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase and metabolic acidosis during fasting, with symptoms (PFK-2/FBPase-2) [45]. Phosphorylation of this enzyme usually manifesting during the frst days of life [60–62]. by cAMP-dependent protein kinase results in inhibi- If not treated appropriately, FBP1 defciency leads to tion of the kinase and activation of the bisphosphatase, unexpected infant death [63]. However, with diet control whereas dephosphorylation has the opposite efect [36, and avoidance of prolonged fasting, most adult patients 40]. TIGAR (TP53-induced glycolysis and apoptosis exhibit relatively normal clinical profles. regulator), a recently identifed enzyme, shares similari- ties with the bisphosphatase domain of PFK-2/FBPase-2 FBPase and type 2 diabetes [46]. TIGAR acts to degrade intracellular F2,6BP [47]. Blood glucose levels are elevated in type 2 diabetes Interestingly, FBP1 and FBP2 difer signifcantly in their (T2DM) due to impaired insulin secretion resulting from kinetic properties. FBP2 is approximately 100 times declining β-cell function; decreased glucose uptake by tis- more susceptible to the allosteric inhibitors AMP and sues such as muscle, liver, and fat; and increased hepatic NAD+ [48] and approximately 1000 times more sensitive glucose production (HGP) [64].
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