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Pyruvate Kinase M2 Regulates Hif 1alfa Activity and IL 1ß Induction and Is a Critical Determinant of the Warburg Effect in LPS Activated Macrophages

Pyruvate Kinase M2 Regulates Hif 1alfa Activity and IL 1ß Induction and Is a Critical Determinant of the Warburg Effect in LPS Activated Macrophages

Macrophages activated by the TLR4 agonist LPS un- dergo dramatic changes in their metabolic activity. We here show that LPS induces expression of the key metabolic regulator Pyruvate Kinase M2 (PKM2). Activation of PKM2 using two well-charac- terized small molecules, DASA-58 and TEPP-46, in- hibited LPS-induced Hif-1a and IL-1b, as well as the expression of a range of other Hif-1a-dependent genes. Activation of PKM2 attenuated an LPS- induced proinflammatory M1 macrophage pheno- type while promoting traits typical of an M2 macrophage. We show that LPS-induced PKM2 en- ters into a complex with Hif-1 a , which can directly bind to the IL-1 b promoter, an event that is inhibited by activation of PKM2. Both compounds inhibited LPS-induced glycolytic reprogramming and succi- nate production. Finally, activation of PKM2 by TEPP-46 in vivo inhibited LPS and Salmonella typhi- murium -induced IL-1 b production, while boosting production of IL-10. PKM2 is therefore a critical determinant of macrophage activation by LPS, pro- moting the inflammatory response.

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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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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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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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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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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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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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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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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

The aerobic glycolysis involves conversion of glucose to lactate and the generation of ATP. Pyruvate kinase catalyzes the final step in glycolysis by transferring the phosphate from phosphoenolpyruvate (PEP) to ADP, thereby generating pyruvate and ATP [11]. The M2 isoform of pyruvate kinase (PKM2) is preferentially expressed in cancer [12] and is a central point of regulator in cancer metabolism [13]. PKM2 promotes the Warburg effect and tumorigenesis [14]. PKM2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1 in cancer [15]. Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cancer cell proliferation [16]. PKM2 could also regulate ß-catenin transactivation, cell proliferation and tumorigenesis in the activation of EGFR [17]. What’s more, PKM2 may confer an additional advantage to cancer cells by allowing them to withstand oxidative stress [18].

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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

Background: Screening programmes exist in many countries for colorectal cancer. In recent years, there has been a drive for a non-invasive screening marker of higher sensitivity and specificity. Stool-based pyruvate kinase isoenzyme M2 (M2-PK) is one such biomarker under investigation. The aim of this systematic review and meta-analysis is to determine the diagnostic accuracy, sensitivity and specificity of M2-PK as a screening tool in colorectal cancer. Methods: A literature search of Ovid Medline, EMBASE and Google Scholar was carried out. The search strategy was restricted to human subjects and studies published in English. Data on sensitivity and specificity were extracted and pooled. Statistical analysis was conducted using summary receiver operating characteristic (SROC) curve methodology. Results: A total of eight studies were suitable for data synthesis and analysis. Our analysis showed a pooled sensitivity and specificity for M2-PK to be 79% (CI 73% – 83%) and 80% (CI 73% – 86%), respectively. The accuracy of M2-PK was 0.85 (0.82 – 0.88).

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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>

Protein expression levels were examined by Western blotting. 22 Total protein was separated from cells or tissues using RIPA lysis buffer (Beyotime Institute of Biotechnology, Shanghai, China) supplemented with phenylmethanesulfonyl fl uoride. The protein concentration was determined with the BCA assay (Beyotime Institute of Biotechnology). Then the samples were subjected to SDS – PAGE, transferred on PVDF membranes, blocked with 5% nonfat milk, and incubated with primary antibodies against proliferating cell nuclear antigen (PCNA; 1:500; Proteintech, Wuhan, China), c-Myc (1:1000; Proteintech), cyclin D1 (1:400; Boster, Wuhan, China), cleaved caspase 3 (1:500; CST, Danvers, MA, USA), cleaved PARP (1:1000; CST), matrix metalloproteinase 2 (MMP-2; 1:500; Proteintech), MMP-9 (1:1000; Proteintech), PK M2 (1:1000; Proteintech), and β -actin (1:500; KeyGEN, Nanjing, China) overnight at 4°C. The membranes were incu- bated with horseradish peroxidase-labeled goat-anti-rabbit /mouse secondary antibodies for 45 min at 37°C. The protein was visualized by the enhanced chemiluminescence (ECL; 7 Sea Biotech, Shanghai, China) under a gel imaging system (Liuyi, Beijing, China). The blots were analyzed by

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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

Activation of HIF-1 commonly occurs in many cancer types and is a driving force regulating many steps in cancer progression [18, 22]. HIF-1 activates the transcription of genes encoding proteins that mediate angiogenesis, invasion, metastasis, and the shift from oxidative to glycolytic metabolism [12, 18, 19, 22, 23]. By activating the transcription of genes encoding glucose transporters and glycolytic enzymes, HIF-1 enhances glucose uptake and glycolysis in cells [23-27]. HIF-1 also controls expression of LDHA and pyruvate dehydrogenase kinase 1 (PDK1) [25, 26, 28, 29]. LDHA catalyzes the conversion of pyruvate to lactate (Figure 1), thereby decreasing mitochondrial utilization of pyruvate as a substrate for pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl coenzyme A (AcCoA). PDK1 phosphorylates the catalytic subunit of PDH, leading to its inactivation, which shunts pyruvate away from the mitochondria. HIF-1 activation shifts the balance of metabolism from oxidative phosphorylation toward glycolysis and mediates the Warburg effect in VHL-null renal carcinoma cells [30].

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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

lation analyses using protein expression and the progression motility as variables, which showed that ACO2 and PKM2 amounts were positively correlated with ejaculate freezability. As an important regulatory enzyme of the tricar- boxylic acid (TCA) cycle, ACO2 catalyzes the reversible hydration of cis-aconitate to yield the isomerization of citrate or isocitrat, which associates with adenosine triphosphate (ATP)- dependent sperm motility [17, 18]. As general- ly accepted, the TCA cycle is known to be a crucial metabolic pathway that contributes to produce ATP to protect spermatozoon against the cryopreservation process in mammalian spermatozoa mitochondria [19]. It is well kno- wn that an adequate supply of energy in the form of ATP is required to support sperm motil- ity [20]. Previously, Wang et al showed that a lower ACO2 expression level was detected in human freeze-thawed spermatozoa compared with normal fresh semen [12]. In addtion, Tang et al also explained the role and mechanism of ACO2 in human sperm motility [21]. Our results showed that the expression level of ACO2 was significantly higher in GFE compared to PFE, which indicated that the degraded ACO2 low- ered the production of isocitrate needed in the TCA cycle. In addition, ACO2 protein expression was significantly correlated with freezability capacity. These results suggested that ACO2 could become a good marker of freezability. PKM2, also known as a key driver of aerobic gly- colysis, controls the final and rate-limiting reac- tion in the glycolytic pathway [14]. Besides, the PKM2 gene, located on chromosome 15q22, encodes a pyruvate kinase that catalyzes the conversion of a phosphoryl group from phos- phoenolpyruvate (PEP) to adenosine diphos- phate (ADP), thereby generating pyruvate and ATP [22-24]. Furthermore, it is well known that ATP plays a crucial role in sperm motility, along with intracellular free calcium [Ca 2+ ]

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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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Endothelial pyruvate kinase M2 maintains vascular integrity

Endothelial pyruvate kinase M2 maintains vascular integrity

PKM1 and PKM2 differ in important ways biochemically. PKM1 functions as a homo-tetramer with constitutively high PK activity. In contrast, PKM2 is regulated by multiple allosteric modulators and posttranslational modifications, each promot- ing either the less active dimer or the more active PKM1-like tetrameric form. PK catalyzes the last step of glycolysis, 1 of 3 rate-limiting steps, and is thus an ideal enzyme to regulate glyco- lytic flux. If the PK activity is low, upper glycolytic intermediates can accumulate and be channeled to various synthetic pathways, including the pentose phosphate pathway necessary for nucleo- tide synthesis and glycogen synthesis. The less active dimeric PKM2 is thus widely thought to promote proliferation by promot- ing shunting of glucose carbons to creation of biomass. Consis- tent with this notion, PKM2 is highly expressed in proliferating cells such as embryonic or cancer cells, whereas PKM1 is usually favored in nonproliferating and terminally differentiated types of cells. TEPP-46, a small molecule activator of PKM2 pyruvate activity, binds to a pocket at the PKM2 subunit interface and pro- motes PKM2 subunits to form stable tetramers. Thus, treatment of TEPP-46 mimics the properties of PKM1 in PKM2-expressing cells. In line with the hypothesis that low PK activity promotes anabolic metabolism to cancer cell proliferation, TEPP-46 has been shown to suppress cancer cell proliferation in vitro and xenograft tumor growth in vivo (8–10).

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Pyruvate kinase M2 is requisite for Th1 and Th17 differentiation

Pyruvate kinase M2 is requisite for Th1 and Th17 differentiation

Co-IP. After Flag-tagged CaMK4/6×His-tagged PKM2 cotransfection, cells were harvested in 1% NP40 lysis buffer. Co-IP was performed with the Dynabeads Protein G Immunoprecipitation Kit (Life Technol- ogies) according to the manufacturer’s protocol. Briefly, cell lysates were prepared as described above, and proteins were immunoprecipitated by incubation of lysates with 4 μg anti-Flag Ab (M2, Sigma-Aldrich), anti-6×His Ab (4E3D10H2/E3, Thermo Fisher Scientific), or control IgG (sc-3877 or sc2025, Santa Cruz Biotechnology) overnight at 4°C and Ab-protein precipitates were pulled down with Dynabeads Protein G. Beads were washed extensively, and proteins were eluted with the elution buffer. The presence of immuno- complexed proteins was determined by Western blotting with anti-Flag Ab and anti-6×His Ab.

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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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The transglutaminase type 2 and pyruvate kinase isoenzyme M2 interplay in autophagy regulation

The transglutaminase type 2 and pyruvate kinase isoenzyme M2 interplay in autophagy regulation

Autophagy is a self-degradative physiological process by which the cell removes worn-out or damaged components. Constant at basal level it may become highly active in response to cellular stress. The type 2 transglutaminase (TG2), which accumulates under stressful cell conditions, plays an important role in the regulation of autophagy and cells lacking this enzyme display impaired autophagy/mitophagy and a consequent shift their metabolism to glycolysis. To further define the molecular partners of TG2 involved in these cellular processes, we analysed the TG2 interactome under normal and starved conditions discovering that TG2 interacts with various proteins belonging to different functional categories. Herein we show that TG2 interacts with pyruvate kinase M2 (PKM2), a rate limiting enzyme of glycolysis which is responsible for maintaining a glycolytic phenotype in malignant cells and displays non metabolic functions, including transcriptional co-activation and protein kinase activity. Interestingly, the ablation of PKM2 led to the decrease of intracellular TG2’s transamidating activity paralleled by an increase of its tyrosine phosphorylation. Along with this, a significant decrease of ULK1 and Beclin1 was also recorded, thus suggesting a block in the upstream regulation of autophagosome formation. These data suggest that the PKM2/TG2 interplay plays an important role in the regulation of autophagy in particular under cellular stressful conditions such as those displayed by cancer cells.

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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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