In this review, we generalized the implication of key enzymes, glucose transporters (GLUTs), signalings and transcription factors in the glycolytic process of glioma. via the above aspects and discussed promising clinical applications for glioma. strong class=”kwd-title” Keywords: aerobic glycolysis, glioma, biological roles, therapeutic interventions, clinical application Introduction Glioma, deriving from neuroepithelial cells, is the most prevalent primary tumor in the central nervous system (CNS), with a proportion of 80% of intracranial malignancies.1 According to World Health Organization (WHO) classification and cellular morphology, gliomas of WHO – could be categorized into several classes including astrocytoma, oligodendroglia, ependymoma, etc.2 Notably, gliomas are characterized by their rapid proliferation, infiltrative growth, treatment resistance, intra- and intertumoral Maraviroc (UK-427857) genetic heterogeneity.3 Despite the fact that most glioma patients could receive maximal safe surgical resection with adjuvant chemotherapy and radiotherapy, the recurrence Rabbit polyclonal to FANK1 rate of them is still high and the prognosis is poor, which is still less than 15 months.4,5 Glycolysis refers to a biological process that glucose or glycogen is decomposed into lactic acid accompanied by moderate production of ATP without ample oxygen.6 Despite the presence of abundant oxygen, cancer cells tend to produce energy via glycolysis even in a higher pace, which was put forward by Otto Warburg, namely the Warburg effect.7 Based on previous studies, key enzymes (HKs, PFK-1, and PKs), glucose transporters (GLUTs) and transcript factors (HIF-1, c-myc, and p53) have been recognized as main regulators in Maraviroc (UK-427857) the glycolytic activities.8 In addition, PI3K/Akt, mTOR, and AMPK signalings were also strongly relevant to glycolysis in multiple solid tumors.9,11 More importantly, the glycolytic process was tightly correlated with various cellular activities, evoking promising therapeutic targets for various tumors.12,13 For instance, lncRNA maternally expressed gene 3 (MEG3) suppressed proliferation and invasion via regulation of glycolysis in colorectal cancer.14 Similarly, the curcumin analogue WZ35 inhibited glycolysis and facilitated the generation of reactive oxygen species (ROS), promoting JNK-dependent apoptosis of gastric cancer cells.15 Xi et al16 also reported that human equilibrative nucleoside transporter 1 (hENT1) was involved in modulating chemotherapy sensitivity of pancreatic cancer cells by inhibiting glycolysis. Recently, gathering investigations have intensively focused on the roles and therapeutic interventions of the glycolytic process in glioma. In this review, we have summarized the roles of key glycolytic enzymes, GLUTs, main signaling pathways, and transcription factors detected in glycolysis of glioma, which may offer possibilities for novel therapies. Implication of Key Enzymes and GLUTs in Aerobic Glycolysis Hexokinases (HKs) HKs catalyze the first step of glycolytic procedure by phosphorylating glucose in the mitochondrial outer membrane of brain and tumor cells, ultimately generating glucose-6-phosphate (G-6-P).17,18 Further gene detection has revealed that HKs exist as five HK isoforms including HKI-IV and HK domain-containing protein 1 (HKDC1), with separate locations of different chromosomes.19 Interestingly, HKII, identified as a housekeeping enzyme, is highly expressed in all mammalian tissues, while the other HKs were characterized with distinct tissue-specificity and differential expression.20 Additionally, HKII has been verified to facilitate glycolysis via multiple central metabolic pathways.21 It was also acknowledged that malignant transformation of neural stem cells was paralleled by overexpression of HKII.22 Recently, accumulating Maraviroc (UK-427857) trials demonstrated that aberrant expression of HKII triggered multiple mechanisms to regulate the progression of multiple solid tumors, especially in glioma.23,25 Noteworthily, HKII knockdown transformed the glycolytic process to oxidative phosphorylation (OXPHOS), accompanied by Maraviroc (UK-427857) the production of ROS in glioma.26 Conversely, a higher glycolytic index along with activated procedures of lipid and protein synthesis was induced by HKII overexpression.27 Nie et al28 also reported that the elevated HKII contributed to an increase in glucose uptake and lactate production in glioma cells with IDH1R132H mutation. Further in vitro experiments illustrated that HKII was significantly upregulated in gliomas and related to proliferation, invasion, apoptosis, and angiogenesis.29 The clonogenic Maraviroc (UK-427857) power and cell-cycle progression of glioma cells were also mediated by misregulation of HKII.27,30 Regarding autophagic death, HKII was confirmed its relevance with glioma cells treated by RSL3, a novel compound of small molecules targeting glutathione peroxidase 4 (GPX4).31 Subsequent functional investigation has been carried out for roles of HKII in glioma, which may emerge as a promising therapeutic target for glioma.
