Pyruvate kinase type M2: A key regulator of the metabolic budget system in tumor cells

Mazurek, Sybille

doi:10.1016/j.biocel.2010.02.005

Cited by 592 publications

(595 citation statements)

References 112 publications

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“…Pyruvate kinase liver red blood enzyme (PKLR) is implicated in the conversion of PEP to pyruvate, specifically in liver and red blood cells. We therefore hypothesized that miR661 may also target the M isoform, which has been described to be highly expressed in cancer cells (Mazurek, 2011). PKM2 increases the diversion of glycolytic intermediates into anabolic pathways, including the pentose phosphate pathway and also slows down ATP generation (Anastasiou et al ., 2011).…”

Section: Resultsmentioning

confidence: 99%

MicroRNA‐661 modulates redox and metabolic homeostasis in colon cancer

et al. 2017

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Cancer cell survival and metastasis are dependent on metabolic reprogramming that is capable of increasing resistance to oxidative and energetic stress. Targeting these two processes can be crucial for cancer progression. Herein, we describe the role of microRNA‐661 (miR661) as epigenetic regulator of colon cancer (CC) cell metabolism. MicroR661 induces a global increase in reactive oxygen species, specifically in mitochondrial superoxide anions, which appears to be mediated by decreased carbohydrate metabolism and pentose phosphate pathway, and by a higher dependency on mitochondrial respiration. MicroR661 overexpression in non‐metastatic human CC cells induces an epithelial‐to‐mesenchymal transition phenotype, and a reduced tolerance to metabolic stress. This seems to be a general effect of miR661 in CC, since metastatic CC cell metabolism is also compromised upon miR661 overexpression. We propose hexose‐6‐phosphate dehydrogenase and pyruvate kinase M2 as two key players related to the observed metabolic reprogramming. Finally, the clinical relevance of miR661 expression levels in stage‐II and III CC patients is discussed. In conclusion, we propose miR661 as a potential modulator of redox and metabolic homeostasis in CC.

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Section: Resultsmentioning

confidence: 99%

MicroRNA‐661 modulates redox and metabolic homeostasis in colon cancer

et al. 2017

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“…I Mor et al phosphorylation of tyrosine residues and proteinprotein interactions, are inhibitory (Hitosugi et al, 2009;Mazurek, 2011). The M2 isoform is expressed during embryonic development and is turned off in adult somatic cells (Hitosugi et al, 2009;Mazurek, 2011).…”

Section: Dapk Regulates Cell Metabolism Through Pkm2mentioning

confidence: 99%

“…The M2 isoform is expressed during embryonic development and is turned off in adult somatic cells (Hitosugi et al, 2009;Mazurek, 2011). A switch in the alternative splicing pattern leads to re-expression of the PKM2 during cancerous transformation and as a consequence, this isoform is almost ubiquitously expressed in tumors and proliferating cell lines (Clower et al, 2010;David et al, 2010).…”

Section: Dapk Regulates Cell Metabolism Through Pkm2mentioning

confidence: 99%

“…Thus, lactate levels can be used to assess glycolytic flux. Additionally, as pyruvate is directly converted to lactate, this product closely correlates with PK activity (Hitosugi et al, 2009;Mazurek, 2011). To validate that PK activity levels correlate with lactate levels, HEK293T cells were transfected with small interfering RNA (siRNA) targeting endogenous PKM2 or with control siRNA.…”

Section: Dapk Regulates Cell Metabolism Through Pkm2mentioning

confidence: 99%

“…Pyruvate kinase is encoded by two genes, which give rise to four highly similar isoforms (Mazurek, 2011). The PKLR gene encodes PKL and PKR through alternative promoter usage yielding two isoform with different N-terminal sequences.…”

Section: Introductionmentioning

confidence: 99%

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Death-associated protein kinase increases glycolytic rate through binding and activation of pyruvate kinase

et al. 2011

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Death-associated protein kinase (DAPk), a multi-domain serine/threonine kinase, regulates numerous cell death mechanisms and harbors tumor suppressor functions. In this study, we report that DAPk directly binds and functionally activates pyruvate kinase M2 (PKM2), a key glycolytic enzyme, which contributes to the regulation of cancer cell metabolism. PKM2 was identified as a novel binding partner of DAPk by a yeast two-hybrid screen. This interaction was validated in vitro by enzyme-linked immunosorbent assay using purified proteins and in vivo by co-immunoprecipitation of the two endogenous proteins from cells. In vitro interaction with full-length DAPk resulted in a significant increase in the activity of PKM2. Conversely, a fragment of DAPk harboring only the functional kinase domain (KD) could neither bind PKM2 in cells nor activate it in vitro. Indeed, DAPk failed to phosphorylate PKM2. Notably, transfection of cells, with a truncated DAPk lacking the KD, elevated endogenous PKM2 activity, suggesting that PKM2 activation by DAPk occurs independently of its kinase activity. DAPk-transfected cells displayed changes in glycolytic activity, as reflected by elevated lactate production, whereas glucose uptake remained unaltered. A mild reduction in cell proliferation was detected as well in these transfected cells. Altogether, this work identifies a new role for DAPk as a metabolic regulator, suggesting the concept of direct interactions between a tumor suppressor and a key glycolytic enzyme to limit cell growth. Moreover, the work documents a unique function of DAPk that is independent of its catalytic activity and a novel mechanism to activate PKM2 by protein-protein interaction.

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Cancer‐associated mutations in human pyruvate kinase M2 impair enzyme activity

et al. 2019

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Mammalian pyruvate kinase catalyzes the final step of glycolysis, and its M2 isoform (PKM2) is widely expressed in proliferative tissues. Mutations in PKM2 are found in some human cancers; however, the effects of these mutations on enzyme activity and regulation are unknown. Here, we characterized five cancer‐associated PKM2 mutations, occurring at various locations on the enzyme, with respect to substrate kinetics and activation by the allosteric activator fructose‐1,6‐bisphosphate (FBP). The mutants exhibit reduced maximal velocity, reduced substrate affinity, and/or altered activation by FBP. The kinetic parameters of five additional PKM2 mutants that have been used to study enzyme function or regulation also demonstrate the deleterious effects of mutations on PKM2 function. Our findings indicate that PKM2 is sensitive to many amino acid changes and support the hypothesis that decreased PKM2 activity is selected for in rapidly proliferating cells.

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Pyruvate kinase type M2: A key regulator of the metabolic budget system in tumor cells

Cited by 592 publications

References 112 publications

MicroRNA‐661 modulates redox and metabolic homeostasis in colon cancer

MicroRNA‐661 modulates redox and metabolic homeostasis in colon cancer

Death-associated protein kinase increases glycolytic rate through binding and activation of pyruvate kinase

Cancer‐associated mutations in human pyruvate kinase M2 impair enzyme activity

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