Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three cell lines established from human gliomas were found to differ in the capacity to phosphorylate the glycolytic enzyme pyruvate kinase in vitro. Phosphorylation in the glioblastoma cell line U-138 was more pronounced than in the glioma cell line Hs 683 and in the glioblastoma cell line A-172. All 3 cell lines showed similar pyruvate kinase isozyme patterns and expressed about 90% K-type and 10% M-type subunits. So, differences in pyruvate kinase phosphorylation could not be explained by differences in the availability of the appropriate substrate, being pyruvate kinase type K. As in gliomas, phosphorylation could specifically and almost completely be inhibited by fructose-1,6-bisphosphate. In order to investigate a potential physiological significance of the phosphorylation of pyruvate kinase, we have characterized these cell lines for several glycolytic parameters. In U-138 cells, the production of lactate appeared to be 2 times higher as compared with A-172 and Hs 683 cells under normal growth conditions and even 4 times higher under low glucose culture regime. The efflux of lactate correlated with the pyruvate kinase phosphorylation pattern in the cell lines. In none of the cell lines could the lactate production be stimulated by glutamine as additional energy source under low glucose culture conditions. The higher glycolytic flux in U-138 cells was not accompanied by higher glycolytic enzyme activities. The isozyme patterns of hexokinase, pyruvate kinase, aldolase, enolase and lactate dehydrogenase in the cell lines were nearly identical and resembled the patterns previously described for solid gliomas. However, the isozyme composition of phosphofructokinase in the cell lines differed from the situation in gliomas. While in gliomas the expression of L-type phosphofructokinase is favored, in the glioma cell lines, we found an increase in the expression of C-type subunits.
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PMID:Phosphorylation of pyruvate kinase and glycolytic metabolism in three human glioma cell lines. 179 9

In primary human brain tumours a shift occurs in the synthesis of isoenzymes of pyruvate kinase from the M towards the K-type. In astrocytomas, oligodendrogliomas and glioblastomas, which were localised in the cerebral hemispheres of adult patients over 20 years of age, the shift correlated well with histological grading and growth rate as observed in postoperative survival. Gliomas of adults, localised in midline structures, as well as childrens gliomas were characterised too by a strong shift from M towards the K type. However, in these tumours, less correlation with histological grading and growth rate was found. The isoenzyme shift can be rapidly demonstrated with an alanine inhibition test. The application of this assay may have a diagnostic value during operation for gliomas in grading of malignancy in adults as well as demarcation of the resection of gliomas in all age groups. The test can be performed within 10-15 min and can thus fit easily into a surgical procedure. A case report is presented for illustration.
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PMID:The pyruvate kinase isoenzyme shift in human gliomas: a potential marker in the treatment of gliomas. 326 8

Malignant gliomas (astrocytomas) are lethal tumors that invade the brain. Invasive cell migration is initiated by extension of pseudopodia into interstitial spaces. In this study, U87 glioma cells formed pseudopodia in vitro as cells pushed through 3 microm pores of polycarbonate membranes. Harvesting pseudopodia in a novel two-step method provided material for proteomic analysis. Differences in the protein profiles of pseudopodia and whole cells were found using differential gel electrophoresis (DIGE) and immunoblotting. Proteins from two-dimensional (2D) gels with M(R)'s of 20-100 kDa and pI's of 3.0-10.0 were identified by peptide mass fingerprinting analysis using mass spectrometry. For DIGE, lysates of pseudopodia and whole cells were each labeled with electrophilic forms of fluorescent dyes, Cy3 or Cy5, and analyzed as mixtures. Analysis was repeated with reciprocal labeling. Differences in protein distributions were detected by manual inspection and computer analysis. Topographical digital maps of the scanned gels were used for algorithmic spot matching, normalization of background, quantifying spot differences, and elimination of artifacts. Pseudopodial proteins in Coomassie-stained 2D gels included isoforms of glycolytic enzymes as the largest group, seven of 24 proteins. Peptide mass fingerprint analysis of DIGE gels demonstrated increased isoforms of annexin (Anx) I, AnxII, enolase, pyruvate kinase, and aldolase, and decreased mitochondrial manganese superoxide dismutase and transketolase in pseudopodia. Specific antibodies showed restricted immunoreactivity of the hepatocyte growth factor (HGF) alpha chain to pseudopodia, indicating localization of its active form. Met (the HGF receptor), actin, and total AnxI were increased in pseudopodial lysates on immunoblots. Increased constituents of the pseudopodial proteome in glioma cells, identified in this study as actin, HGF, Met, and isoforms of AnxI, AnxII, and several glycolytic enzymes, represent therapeutic targets to consider for suppression of tumor invasion.
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PMID:Proteomic characterization of harvested pseudopodia with differential gel electrophoresis and specific antibodies. 1565 57

Emerging studies have identified microRNAs (miRNAs) as possible therapeutic tools for the treatment of glioma, the most aggressive brain tumor. Their important targets in this tumor are not well understood. We recently found that the Notch pathway is a target of miRNA-326. Ectopic expression of miRNA-326 in glioma and glioma stem cells induced their apoptosis and reduced their metabolic activity. Computational target gene prediction revealed pyruvate kinase type M2 (PKM2) as another target of miRNA-326. PKM2 has recently been shown to play a key role in cancer cell metabolism. To investigate whether it might be a functionally important target of miR-326, we used RNA interference to knockdown PKM2 expression in glioma cells. Transfection of the established glioma and glioma stem cells with PKM2 siRNA reduced their growth, cellular invasion, metabolic activity, ATP and glutathione levels, and activated AMP-activated protein kinase. The cytotoxic effects exhibited by PKM2 knockdown in glioma and glioma stem cells were not observed in transformed human astrocytes. Western blot analysis of human glioblastoma specimens showed high levels of PKM2 protein, but none was observed in normal brain samples. Strikingly, cells with high levels of PKM2 expressed lower levels of miR-326, suggestive of endogenous regulation of PKM2 by miR-326. Our data suggest PKM2 inhibition as a therapy for glioblastoma, with the potential for minimal toxicity to the brain.
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PMID:Pyruvate kinase M2 is a target of the tumor-suppressive microRNA-326 and regulates the survival of glioma cells. 2066 97

Gliomas contain a small number of treatment-resistant glioma stem cells (GSCs), and it is thought that tumor regrowth originates from GSCs, thus rendering GSCs an attractive target for novel treatment approaches. Cancer cells rely more on glycolysis than on oxidative phosphorylation for glucose metabolism, a phenomenon used in 2-[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography imaging of solid cancers, and targeting metabolic pathways in cancer cells has become a topic of considerable interest. However, if GSCs are indeed important for tumor control, knowledge of the metabolic state of GSCs is needed. We hypothesized that the metabolism of GSCs differs from that of their progeny. Using a unique imaging system for GSCs, we assessed the oxygen consumption rate, extracellular acidification rate, intracellular ATP levels, glucose uptake, lactate production, PKM1 and PKM2 expression, radiation sensitivity, and cell cycle duration of GSCs and their progeny in a panel of glioma cell lines. We found GSCs and progenitor cells to be less glycolytic than differentiated glioma cells. GSCs consumed less glucose and produced less lactate while maintaining higher ATP levels than their differentiated progeny. Compared with differentiated cells, GSCs were radioresistant, and this correlated with a higher mitochondrial reserve capacity. Glioma cells expressed both isoforms of pyruvate kinase, and inhibition of either glycolysis or oxidative phosphorylation had minimal effect on energy production in GSCs and progenitor cells. We conclude that GSCs rely mainly on oxidative phosphorylation. However, if challenged, they can use additional metabolic pathways. Therefore, targeting glycolysis in glioma may spare GSCs.
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PMID:Metabolic state of glioma stem cells and nontumorigenic cells. 2190 Jun 5

Although considerable progress has been made toward understanding glioblastoma biology through large-scale genetic and protein expression analyses, little is known about the underlying metabolic alterations promoting their aggressive phenotype. We conducted global metabolomic profiling on patient-derived glioma specimens and identified specific metabolic programs differentiating low- and high-grade tumors, with the metabolic signature of glioblastoma reflecting accelerated anabolic metabolism. When coupled with transcriptional profiles, we identified the metabolic phenotype of the mesenchymal subtype to consist of accumulation of the glycolytic intermediate phosphoenolpyruvate and decreased pyruvate kinase activity. Unbiased hierarchical clustering of metabolomic profiles identified three subclasses, which we term energetic, anabolic, and phospholipid catabolism with prognostic relevance. These studies represent the first global metabolomic profiling of glioma, offering a previously undescribed window into their metabolic heterogeneity, and provide the requisite framework for strategies designed to target metabolism in this rapidly fatal malignancy.
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PMID:The metabolomic signature of malignant glioma reflects accelerated anabolic metabolism. 2302 33

Normal tissues express the M1 isoform of pyruvate kinase (PK) that helps generate and funnel pyruvate into the mitochondria for ATP production. Tumors, in contrast, express the less active PKM2 isoform, which limits pyruvate production and spares glycolytic intermediates for the generation of macromolecules needed for proliferation. Although high PKM2 expression and low PK activity are considered defining features of tumors, very little is known about how PKM expression and PK activity change along the continuum from low grade to high grade tumors, and how these changes relate to tumor growth. To address this issue, we measured PKM isoform expression and PK activity in normal brain, neural progenitor cells, and in a series of over 100 astrocytomas ranging from benign grade I pilocytic astrocytomas to highly aggressive grade IV glioblastoma multiforme (GBM). All glioma exhibited comparably reduced levels of PKM1 expression and PK activity relative to normal brain. In contrast, while grade I-III gliomas all had modestly increased levels of PKM2 RNA and protein expression relative to normal brain, GBM, regardless of whether they arose de novo or progressed from lower grade tumors, showed a 3-5 fold further increase in PKM2 RNA and protein expression. Low levels of PKM1 expression and PK activity were important for cell growth as PKM1 over-expression and the accompanying increases in PK activity slowed the growth of GBM cells. The increased expression of PKM2, however, was also important, because shRNA-mediated PKM2 knockdown decreased total PKM2 and the already low levels of PK activity, but paradoxically also limited cell growth in vitro and in vivo. These results show that pyruvate kinase M expression, but not pyruvate kinase activity, is regulated in a grade-specific manner in glioma, but that changes in both PK activity and PKM2 expression contribute to growth of GBM.
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PMID:Pyruvate kinase M2 expression, but not pyruvate kinase activity, is up-regulated in a grade-specific manner in human glioma. 2345 Dec 52

Glioma stem cells are highly resistant to cell death and as such are supposed to contribute to tumor recurrence by eluding anticancer treatments. Here, we show that spheroids that contain rat neural stem cells (NSCs) or rat glioma stem cells (cancer stem cells, CSCs) express isoforms 1 and 2 of pyruvate kinase (PKM1 and PKM2); however, the expression of PKM2 is considerably higher in glioma spheroids. Silencing of PKM2 enhances both apoptosis and differentiation of rat and human glioma spheroids. We establish that PKM2 was implicated in glioma spheroid differentiation through its interaction with Oct4, a major regulator of self-renewal and differentiation in stem cells. The small molecule Dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor, increases the amount of PKM2/Oct4 complexes and thus inhibited Oct4-dependent gene expression. Taken together, our results highlight a new molecular pathway through which PKM2 can manage gliomagenesis via the control of glioma stemness by Oct4.
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PMID:Control of glioma cell death and differentiation by PKM2-Oct4 interaction. 2448 50

Oxidative stress serves as an important regulator of both apoptosis and metabolic reprogramming in tumor cells. Chaetocin, a histone methyltransferase inhibitor, is known to induce ROS generation. As elevating basal ROS level sensitizes glioma cells to apoptosis, the ability of Chaetocin in regulating apoptotic and metabolic adaptive responses in glioma was investigated. Chaetocin induced glioma cell apoptosis in a ROS-dependent manner. Increased intracellular ROS induced (i) Yes-associated protein 1 (YAP1) expression independent of the canonical Hippo pathway as well as (ii) ATM and JNK activation. Increased interaction of YAP1 with p73 and p300 induced apoptosis in an ATM-dependent manner. Chaetocin induced JNK modulated several metabolic parameters like glucose uptake, lactate production, ATP generation, and activity of glycolytic enzymes hexokinase and pyruvate kinase. However, JNK had no effect on ATM or YAP1 expression. Coherent with the in vitro findings, Chaetocin reduced tumor burden in heterotypic xenograft glioma mouse model. Chaetocin-treated tumors exhibited heightened ROS, pATM, YAP1 and pJNK levels. Our study highlights the coordinated control of glioma cell proliferation and metabolism by ROS through (i) ATM-YAP1-driven apoptotic pathway and (ii) JNK-regulated metabolic adaptation. The elucidation of these newfound connections and the roles played by ROS to simultaneously shift metabolic program and induce apoptosis could provide insights toward the development of new anti-glioma strategies.
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PMID:Chaetocin-induced ROS-mediated apoptosis involves ATM-YAP1 axis and JNK-dependent inhibition of glucose metabolism. 2481 48

The M2 isoform of pyruvate kinase is expressed preferentially in cancer cells over other pyruvate kinase isoforms. PKM2 is unique in its ability to be regulated allosterically by nutrients and growth signaling pathways, allowing cells to adapt their metabolic program to match physiological needs in different environments. Here, we discuss the role of pyruvate kinase M2 in glioma and in cancer metabolism.
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PMID:The Role of Pyruvate Kinase M2 in Cancer Metabolism. 2652 46


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