Pyruvate kinase M2 (PKM2)

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Original Article Both high expression of pyruvate kinase M2 and vascular endothelial growth factor-C predicts poorer prognosis in human breast cancer

Original Article Both high expression of pyruvate kinase M2 and vascular endothelial growth factor-C predicts poorer prognosis in human breast cancer

Abstract: Pyruvate kinase M2 (PKM2) and vascular endothelial growth factor-C (VEGF-C) have been known to play an important role in tumorigenesis and tumor progression in breast cancer. However, the association between PKM2 and VEGF-C in breast cancer remains unclear. In the present study, a total of 218 specimens from breast cancer patients and 26 paired breast tumors with adjacent normal tissues as well as two breast cancer cell lines were enrolled to investigate the correlation between PKM2 and VEGF-C. We found that PKM2 and VEGF-C mRNA levels were both significantly increasing in breast tumors compared with adjacent normal tissues. Knockdown of PKM2 mRNA expression resulted in VEGF-C mRNA and protein down-regulated as well as cell proliferation inhib- ited. A positive correlation between PKM2 and VEGF-C expression was identified by immunohistochemical analyses of 218 specimens of patients with breast cancer (P=0.023). PKM2 high expression was significantly correlated with histological grade (P=0.030), lymph node stage (P=0.001), besides VEGF-C high expression was significantly associated with lymphovascular invasion (P=0.012). While combined high expression of PKM2 and VEGF-C was found to be associated with worse histological grade, more lymph node metastasis, more lymphovascular invasion, shorter progression free survival (PFS), and poorer overall survival (OS) in human breast cancer. The results of the present study suggested that PKM2 expression was correlated with VEGF-C expression, and combination of PKM2 and VEGF-C levels had the better prognostic significance in predicting the poor outcome of patients with breast cancer.
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Expression of pyruvate kinase M2 in human bladder cancer and its correlation with clinical parameters and prognosis

Expression of pyruvate kinase M2 in human bladder cancer and its correlation with clinical parameters and prognosis

Notes: (A–D) representative PKM2 and h&e stains are shown. Positivity for PKM2 was observed primarily in the cytoplasm. (A and B) adjacent normal bladder tissues observed by h&e staining (×40). (C and D) Bladder cancer tissues observed by h&e staining (×40). (E) high and (F) low expression of PKM2 in adjacent normal bladder tissues observed by ihc (×40). (G) high and (H) low expression of PKM2 in bladder cancer tissues observed by ihc (×40). (I and K) relative expression of PKM2 protein detected by Western blot in 10 UcB cases. expression levels were normalized to β-actin. (J) relative expression of PKM2 mrna detected by real-time-Pcr in 10 UcB cases. *P,0.001. Abbreviations: PKM2, pyruvate kinase M2; UcB, urothelial carcinoma of the bladder; h&e, hematoxylin and eosin; ihc, immunohistochemistry; Pcr, polymerase chain reaction; RQ, relative quantification; c, bladder cancer tissues; n, normal bladder tissues.
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Original Article Expression of pyruvate kinase M2 in human colorectal cancer and its prognostic value

Original Article Expression of pyruvate kinase M2 in human colorectal cancer and its prognostic value

Colorectal cancer (CRC) is currently one of the most common causes of cancer-related death worldwide, and the most frequent malignancies in the gastrointestinal tract [1]. Due to western- ized dietary lifestyle, the incidence of CRC is increasing in several Asian countries [2, 3]. Although great improvements are achieved in early diagnosis, surgical management and tar- geted therapeutic strategies, the prognosis of CRC patients is still extremely poor because of distant metastasis [4]. Therefore, it would ben- eficial to identify novel predictor for better diag- nosis and prognosis of this deadly disease. Reprogramming energy metabolism is an emerging hallmark of cancer cells [5]. Tumor cells favor glycolysis and little pyruvate is dis- patched to mitochondria for oxidative phos- phorylation even in the presence of sufficient oxygen. Pyruvate kinase M2 (PKM2), a key met-
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Pyruvate kinase M2 prevents apoptosis via modulating Bim stability and associates with poor outcome in hepatocellular carcinoma

Pyruvate kinase M2 prevents apoptosis via modulating Bim stability and associates with poor outcome in hepatocellular carcinoma

Pyruvate kinase M2 (PKM2) contributes to the Warburg effect, a hallmark of cancer. We showed that PKM2 levels were correlated with overall survival (hazard ration = 1.675, 95% confidence interval: 1.389–2.019, P < 0.001) and disease-free survival (hazard ration = 1.573, 95% confidence interval: 1.214–2.038, P < 0.001) in a cohort of 490 patients with HCC. The correlations were further validated in an independent cohort of 148 HCC patients. Multivariate analyses revealed that PKM2 was an independent indicator of poor outcome in HCC. The knockdown of PKM2 in HCC cells inhibited cell proliferation and induced apoptosis in vitro and in vivo. Bim siRNA markedly abolished the PKM2-depletion-induced apoptosis. PKM2 depletion decreased the degradation of Bim. In clinical samples, PKM2 expression was reversely correlated with Bim expression. Combination of PKM2 and Bim levels had the best prognostic significance. We suggest that PKM2 serves as a promising biomarker for poor prognosis of patients with HCC and its knockdown induces HCC apoptosis by stabilizing Bim.
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<p>Phosphoribosyl Pyrophosphate Amidotransferase Promotes the Progression of Thyroid Cancer via Regulating Pyruvate Kinase M2</p>

<p>Phosphoribosyl Pyrophosphate Amidotransferase Promotes the Progression of Thyroid Cancer via Regulating Pyruvate Kinase M2</p>

PPAT is con fi rmed to be highly expressed in lung adenocarci- noma tissues; overexpression of PPAT signi fi cantly promotes tumor cell proliferation and invasion via activating pyruvate kinase (PK) and can function as a biomarker for aggressive lung adenocarcinoma. 11 However, the expression and function of PPAT in TC and its mechanism have not yet been elucidated. PK is a rate-limiting enzyme in the glycolytic pathway. It catalyzes the substrate phosphoenolpyruvate (PEP) to pro- duce pyruvate and release energy. It can encode four isoen- zymes, and among them, pyruvate kinase M2 (PKM2) is reported to be a key regulator of tumor cell metabolism, growth, and metastasis. 12,13 With the up-regulation of PKM2, the enzyme structure changes from a traditional tet- ramer to a dimer, which has a weaker af fi nity for PEP, leading to changes in tumor cell metabolism, thus allowing tumor cells to proliferate with limited nutritional supply. 14,15 Many studies show that PKM2 is increased in a variety of human cancers. PKM2 plays a crucial regulatory role in the carci- nogenesis, proliferation, migration, and invasion of tumor cells. For example, in hepatocellular carcinoma, PKM2 inter- acts with the nuclear sterol regulatory element-binding pro- tein 1a (SREBP-1 α ) to activate adipogenesis and promote cell proliferation; highly expressed PKM2 is signi fi cantly associated with poor prognosis of patients with liver cancer. 16,17 PKM2 is signi fi cantly overexpressed in gallblad- der cancer tissues, and up-regulation of PKM2 can promote tumorigenesis. 18 It is also reported that PKM2 is involved in the progression of TC. 19 Additionally, the activation or up- regulation of PKM2 could activate multiple cancer-related pathways such as ERK signaling and STAT3 signaling. 20–22 However, the expression of PKM2 in TC and its related mechanisms remain to be further explored.
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Original Article Aconitate 2 (ACO2) and pyruvate kinase M2 (PKM2) are good predictors of human sperm freezability

Original Article Aconitate 2 (ACO2) and pyruvate kinase M2 (PKM2) are good predictors of human sperm freezability

linked this aspect with genetic differences in human semen samples, and amplified frag- ment length polymorphisms have also been suggested as freezability predictors in terms of variation of post-thaw sperm quality [11]. Proteomic techniques have been extensively applied in terms of human sperm cryopreserva- tion, and some proteins have been found to be probable predictive markers of sperm freeza- bility, like enolase1 (ENO1), vimentin (VIM) and tektin-1 (TEKT1) [12]. Therefore, these findings suggested that we could find specific proteins of human ejaculates as good predictive mark- ers to assess human sperm freezing capaci- ty. Sperm motility need adequate supply of en- ergy in the form of ATP and glycolysis plays a vital role in energy metabolism. Mitochondri- al aconitate (ACO2) and pyruvate kinase M2 (PKM2) are closely related to glucose metabo- lism and our previous study showed these two proteins had marked differences between the fresh and freeze-thawed sperm samples [12- 14]. Therefore, we selected ACO2 and PKM2 as research objects to find specific proteins of human sperm freezing capacity.
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Leptin promotes epithelial-mesenchymal transition of breast cancer via the upregulation of pyruvate kinase M2

Leptin promotes epithelial-mesenchymal transition of breast cancer via the upregulation of pyruvate kinase M2

that leptin could promote EMT in breast cancer cells [20], and IL-8 was one of the key molecules which affected leptin-mediated EMT. To explore other key regulatory molecules that are involved in leptin-induced EMT of breast cancer cells, gene expression chip array was con- ducted, which found that a series of enzymes related to glycometabolism increased in breast cancer cells, such as PGK1, PGAM2, PDK2, SUCLG1, DLST, and PKM2. As one of the most increased molecules, PKM2 was verified to increase significantly in MCF-7 and SK-BR-3 cells treated with leptin. Thereby, we hypothesized that leptin promoted epithelial-mesenchymal transition of breast cancer cells via the upregulation of pyruvate kinase M2.
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Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to the development of pulmonary arterial hypertension

Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to the development of pulmonary arterial hypertension

Aims: Pulmonary arterial hypertension[1] is a proliferative disorder associated with enhanced proliferation and suppressed apoptosis of pulmonary artery smooth muscle cells (PASMCs). Reactive oxygen species (ROS) is implicated in the development of PAH and regulates the vascular tone and functions. However, which cellular signaling mechanisms are triggered by ROS in PAH is still unknown. Hence, here we wished to characterize the signaling mechanisms triggered by ROS. Methods and Results: By western blots, we showed that increased intracellular ROS caused inhibition of the glycolytic pyruvate kinase M2 (PKM2) activity through promoting the phosphorylation of PKM2. Monocrotaline (MCT)-induced rats developed severe PAH and right ventricular hypertrophy, with a significant increase in the P-PKM2 and decrease in pyruvate kinase activity which could be attenuated with the treatments of PKM2 activators, FBP and L-serine. The antioxidant NAC, apocynin and MnTBAP had the similar protective effects in the development of PAH. In vitro assays confirmed that inhibition of PKM2 activity could modulate the flux of glycolytic intermediates in support of cell proliferation through the increased pentose phosphate pathway (PPP). Increased ROS and decreased PKM2 activity also promoted the Cav1.2 expression and intracellular calcium.
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Targeting stromal-induced pyruvate kinase M2 nuclear translocation impairs OXPHOS and prostate cancer metastatic spread

Targeting stromal-induced pyruvate kinase M2 nuclear translocation impairs OXPHOS and prostate cancer metastatic spread

Cancer associated fibroblasts (CAFs) are key determinants of cancer progression. In prostate carcinoma (PCa), CAFs induce epithelial-mesenchymal transition (EMT) and metabolic reprogramming of PCa cells towards oxidative phosphorylation (OXPHOS), promoting tumor growth and metastatic dissemination. We herein establish a novel role for pyruvate kinase M2 (PKM2), an established effector of Warburg-like glycolytic behavior, in OXPHOS metabolism induced by CAFs. Indeed, CAFs promote PKM2 post-translational modifications, such as cysteine oxidation and Src-dependent tyrosine phosphorylation, allowing nuclear migration of PKM2 and the formation of a trimeric complex with hypoxia inducible factor-1α (HIF-1α) and the transcriptional repressor Differentially Expressed in Chondrocytes-1 (DEC1). DEC1 recruitment is mandatory for downregulating miR205 expression, thereby fostering EMT execution and metabolic switch toward OXPHOS. Furthermore, the analysis of a cohort of PCa patients reveals a significant positive correlation between PKM2 nuclear localization and cancer aggressiveness, thereby validating our in vitro observations. Crucially, in vitro and in vivo pharmacological targeting of PKM2 nuclear translocation using DASA-58, as well as metformin, impairs metastatic dissemination of PCa cells in SCID mice. Our study indicates that impairing the metabolic tumor:stroma interplay by targeting the PKM2/OXPHOS axis, may be a valuable novel therapeutic approach in aggressive prostate carcinoma.
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Small ubiquitin-like modifier 1 modification of pyruvate kinase M2 promotes aerobic glycolysis and cell proliferation in A549 human lung cancer cells

Small ubiquitin-like modifier 1 modification of pyruvate kinase M2 promotes aerobic glycolysis and cell proliferation in A549 human lung cancer cells

0.73±0.11, P=0.032). (D) A549 cells were transfected with HA-tagged PKM2-WT or K336R. After 24 h of transfection, the cells were replated into appropriate plates for analysis of basal oxygen consumption rate by a Seahorse XF24 extracellular flux analyzer (Agilent, Santa Clara, CA, USA). (E) K336R mutant increased PKM2 enzyme activity. (F) Activation of the HIF-1-luc reporter by WT-PKM2 and K336R-PKM2 in the presence of Flag-SUMO1 and si-SUMO1. (G) The mRNA levels of HIF-1 targeted genes in A549 cells transfected with HA-tagged PKM2-WT or K336R were analyzed by real-time polymerase chain reaction. (Data represent mean ± sD n=3), *P0.05, **P0.01. Abbreviations: 18 F-FDg, 18 F-deoxyglucose; HA, hemagglutinin; HIF, hypoxia inducible factor; PKM2, pyruvate kinase M2; SUMO1, small ubiquitin-like modifier 1; SUVmax,
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Pyruvate kinase M2 is requisite for Th1 and Th17 differentiation

Pyruvate kinase M2 is requisite for Th1 and Th17 differentiation

and transfected with Pkm2-shRNA or control shRNA and transferred into Rag1-deficient mice. The mice that received Pkm2-shRNA–transfected 2D2 T cells exhibited reduced EAE disease activity com- pared with those that received cells transfected with control shRNA (Figure 6, A and B). To confirm Figure 4. PKM2 inhibitor ameliorates EAE. (A–G) EAE was induced in B6 mice by immunization with MOG35-55 emulsified in complete Freund’s adjuvant. Mice were treated with DMSO or shikonin twice a week intraperitoneally. (A) Clinical scores. (B) Body weight changes. Cumulative results of 2 independent experiments with 5 mice per group are shown (mean ± SEM); n = 10. (C and D) Spinal cords were harvested on day 14 and stained with H&E to evaluate inflammation. (C) Representative images show H&E staining of spine from DMSO- or shikonin-treated mice. Scale bars: 500 μm or 100 μm (higher-magnifi- cation images on right). (D) Quantitative cumulative data are shown (mean ± SEM); n = 5. (E–G) Absolute cell numbers of spinal cord–infiltrating CD4 + T cells (E), IFN-γ–producing (F), and IL-17A–producing CD4 + T cells (G) from DMSO- or shiko-
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<p>Antitumor Effect of miR-1294/Pyruvate Kinase M2 Signaling Cascade in Osteosarcoma Cells</p>

<p>Antitumor Effect of miR-1294/Pyruvate Kinase M2 Signaling Cascade in Osteosarcoma Cells</p>

miRNAs mainly function as negative regulators of gene expression. Our research revealed that miR-1294 regulated PKM2 expression by direct interaction with its 3 ʹ UTR. Re-induction of PKM2 reversed the inhibitory actions of miR-1294 mimic on osteosarcoma cells. It has been reported that PKM2 is increased and its knockdown inhibits survival and invasion of osteosarcoma cells. 17,23 Other miRNAs including miR-133b, 30 miR-214, 31 and miR-139-5p 32 have been implicated in inhibiting cancer cell growth by downregulation of PKM2. Moreover, it is also known that PKM2 contributes to tumor metabolism. 33,34 In consideration of the association between PKM2 and miR-1294, it is possible that miR- 1294 plays a role in the metabolism of osteosarcoma. In addition, multiple pathways are involved in the regulation
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Endothelial pyruvate kinase M2 maintains vascular integrity

Endothelial pyruvate kinase M2 maintains vascular integrity

The different siRNAs achieved variable suppression of PKM2 mRNA and protein expression (Figure 2, A and B). PKM1 expres- sion was mildly or not at all increased (Figure 2, A and B). Strik- ingly, suppression of PKM2 led to dose-dependent inhibition of cellular proliferation, in proportion to the extent of PKM2 suppres- sion (Figure 2C). siRNA27, the most efficient at suppressing PKM2 (labeled siPKM2 from here on), led to complete growth arrest (Fig- ure 2C) and a near-complete block of BrdU incorporation (Figure 2D), demonstrating a block of entry into S phase. Other duplex siRNAs, si87 and si155, had similar effects on BrdU incorporation (Supplemental Figure 1B). siPKM2 did not, however, promote cell death (Figure 2E), indicating a block specifically in cell prolifera- tion. ECs have various unique properties germane to their ability to form new blood vessels, including a strong capacity for migra- tion and spontaneous tube formation. Both these properties were profoundly suppressed by siPKM2 (and si87 and si155), as shown by transwell migration assay (Figure 2F and Supplemental Fig- ure 1C), scratch closure assay (Figure 2G and Supplemental Fig-
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Pyruvate kinase M2 overexpression and poor prognosis in solid tumors of digestive system: evidence from 16 cohort studies

Pyruvate kinase M2 overexpression and poor prognosis in solid tumors of digestive system: evidence from 16 cohort studies

Studies were eligible if 1) they reported the relationship between PKM2 expression and OS, which was defined as the time from surgery to the date of all-cause death or last follow-up; 2) they used a cohort design; 3) they used immunohistochemical (IHC) method to detect PKM2 protein expression; and 4) hazard ratios (HRs) and 95% confidence intervals (CIs) could be directly obtained or indirectly calculated from the original data. Studies were ineligible if they were reviews, conference abstracts, editorials or case reports, or were conducted on nonhumans and if the articles had insufficient data to estimate HRs and 95% CIs. We also examined all authors’ names and the medical centers involved to avoid duplication of data. If more than one publication with the same study population was identified, only the most recent data were included in the final analysis.
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Pyruvate kinase M2 and the mitochondrial ATPase Inhibitory Factor 1 provide novel biomarkers of dermatomyositis: a metabolic link to oncogenesis

Pyruvate kinase M2 and the mitochondrial ATPase Inhibitory Factor 1 provide novel biomarkers of dermatomyositis: a metabolic link to oncogenesis

distinctive feature of cancer cells is the enhanced aero- bic glycolysis [14, 27]. Pyruvate kinase (PK) is the enzyme that catalyzes the final step in glycolysis, converting phos- phoenolpyruvate (PEP) to pyruvate [28]. Four different isoforms of pyruvate kinase exist: type-R and type-L are generated by alternative splicing of the PKLR gene and are expressed in erythrocytes and in liver, respectively [29]. PKM1 is the isoform expressed in adult skeletal muscle while PKM2, which results from alternative splicing of the PKM gene is expressed exclusively in embryonic and pro- liferating tissues. Notably, PKM2 is allosterically regulated due to its possibility to switch from a dimeric low-active form to a tetrameric very high active form [30–32]. In addition, phosphorylation of S37 and Y105 in PKM2 pre- vents the binding of the PKM2 cofactor fructose-1,6-bi- sphosphate, thus inhibiting the active tetrameric form of PKM2 which promotes aerobic glycolysis and tumor growth [33] (Fig. 5). Our findings stress the idea that DM triggers an increase in the expression of PKM2 rather than a switch in the expression of muscle isoforms. Like- wise, the increased expression of PKM2 in muscle of DM patients is in its non-phosphorylated active state. Moreo- ver, PKM2 also has a “non-metabolic” role in tumorigen- esis since its translocation into the nucleus regulates gene transcription of several pathways involved in metabolic reprogramming, cell proliferation and cancer develop- ment [34–37]. Although we did not observe any nuclear localization of PKM2 in muscle of DM patients, we can- not exclude this possibility (Fig.  7) because its nuclear translocation might represent a late event in the pro- oncogenic development of the disease.
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Pyruvate kinase M2 regulates glucose metabolism by functioning as a coactivator for hypoxia-inducible factor 1 in cancer cells

Pyruvate kinase M2 regulates glucose metabolism by functioning as a coactivator for hypoxia-inducible factor 1 in cancer cells

PK catalyzes the conversion of phosphoenolpyruvate to pyruvate (Figure 1) and is composed of M1-/M2-type and L-/R-type isoforms, which are encoded by PKM2 and PKLR genes, respectively [31]. Tissue-specific promoters control expression of PKL, which is expressed in liver and kidney, and PKR, which is expressed in erythrocytes. PKM1 and PKM2 are the alternatively spliced products of the PKM2 primary RNA transcript with PKM1 and PKM2 mRNA containing sequences encoded by exon 9 or exon 10, respectively [32]. PKM1 is expressed in muscle and brain, whereas PKM2 is expressed in the embryo and in cancer cells. The transcription factors Sp1 and Sp3 bind to a GC-rich element in the promoter of the human PKM2 gene [33]. Sp1 constitutively activates transcription of PKM2, whereas Sp3 functions as a transcriptional repressor that dissociates from the PKM2 gene under hypoxic conditions.
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Warburg effect hypothesis in autism Spectrum disorders

Warburg effect hypothesis in autism Spectrum disorders

overexpression of the canonical WNT/ β -catenin pathway in ASD. Upregulation of WNT/ β -catenin pathway induces aerobic glycolysis, named Warburg effect, through activation of glucose transporter (Glut), pyruvate kinase M2 (PKM2), pyruvate dehydrogenase kinase 1(PDK1), monocarboxylate lactate transporter 1 (MCT-1), lactate dehydrogenase kinase-A (LDH-A) and inactivation of pyruvate dehydrogenase complex (PDH). The aerobic glycolysis consists to a supply of a large part of glucose into lactate regardless of oxygen. Aerobic glycolysis is less efficient in terms of ATP production than oxidative phosphorylation because of the shunt of the TCA cycle. Dysregulation of energetic metabolism might promote cell deregulation and progression of ASD. Warburg effect regulation could be an attractive target for developing therapeutic interventions in ASD.
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Complex role of HIF in cancer: the known, the unknown, and the unexpected

Complex role of HIF in cancer: the known, the unknown, and the unexpected

Figure 2 Role of hypoxia-inducible factor 1 (HiF-1) in regulating bioenergetics and biosynthesis through the induction of pyruvate kinase M2 (PKM2) in proliferating cancer cells. Notes: increased HiF-1 expression through oncogenic signaling not only promotes glucose uptake and glycolysis, but also cooperates with c-Myc to increase PKM2 expression through transcriptional upregulation of PKM and PKM2 splicing, respectively. PKM2 is present mainly in the nucleus as a dimer and acts as a protein kinase to drive gene transcription for cell-cycle progression. its low activity as pyruvate kinase blunts the conversion of phosphoenolpyruvate (PeP) to pyruvate, thereby diverting upstream glycolytic metabolites into the biosynthesis pathways. Although PKM2 can also exist as a tetramer for glycolysis, its glycolytic activity is inhibited by oncogenic signaling.
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A systematic review and meta analysis of the diagnostic accuracy of pyruvate kinase M2 isoenzymatic assay in diagnosing colorectal cancer

A systematic review and meta analysis of the diagnostic accuracy of pyruvate kinase M2 isoenzymatic assay in diagnosing colorectal cancer

Articles with sensitivity and specificity results of faecal M2-PK for colorectal cancer with confirmation of cancer using colonoscopy and histology were included in our study. Studies on plasma M2-PK, adenoma only, func- tional bowel disorders only and inflammatory bowel dis- eases only were excluded along with posters, systematic reviews, meta-analysis, articles not in English and other gastrointestinal cancers. Quality assessment of the in- cluded studies was carried out using ‘QUADAS’ scoring system (Table 1).

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Nonmetabolic functions of metabolic enzymes in cancer development

Nonmetabolic functions of metabolic enzymes in cancer development

Metabolic enzymes function as protein kinases Protein kinases are critical regulators of intracellular signal transduction pathways that mediate various cel- lular processes in both unicellular and multicellular organisms. They can directly transfer the γ-phosphate from adenosine triphosphate (ATP) to specific tyros- ine (Tyr), serine (Ser), threonine (Thr), and histidine (His) residues on substrate proteins, thereby altering the functions of these substrates. More than 500 protein kinases have been identified in humans, constituting of about 1.7% of all human genes [5]. Recent studies have demonstrated that several metabolic enzymes, such as pyruvate kinase M2 (PKM2), phosphoglycerate kinase 1 (PGK1), ketohexokinase-A (KHK-A), hexokinases (HK), nucleoside diphosphate kinase (NDPK or NDK), and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4), have unexpected protein kinase activities and play significant roles in nonmetabolic cellular functions. These new studies expand the family of protein kinases and provide new insights into the integrated regulation of cell metabolism and other cellular processes.
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