Pyruvate kinase type M2 and its role in tumor growth and spreading

Mazurek, Sybille; Boschek, C. B.; Hugo, F; Eigenbrodt, Erich

doi:10.1016/j.semcancer.2005.04.009

Cited by 707 publications

(725 citation statements)

References 55 publications

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“…Transformed cells express an alternative splice form of pyruvate kinase (PKM2), which is usually restricted to embryonic and proliferating tissue and displays reduced catalytic activity [57]. In mouse xenograft experiments, altering the PK expression pattern so that cancer cells expressed only the PKM1 isoform dramatically slowed tumour progression and reactivated respiration [58].…”

Section: Reviewmentioning

confidence: 99%

Regulatory crosstalk of the metabolic network

Grüning

Lehrach

Ralser

2010

Trends in Biochemical Sciences

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The metabolic network has a modular architecture, is robust to perturbations, and responds to biological stimuli and environmental conditions. Through monitoring by metabolite responsive macromolecules, metabolic pathways interact with the transcriptome and proteome. Whereas pathway interconnecting cofactors and substrates report on the overall state of the network, specialised intermediates measure the activity of individual functional units. Transitions in the network affect many of these regulatory metabolites, facilitating the parallel regulation of the timing and control of diverse biological processes. The metabolic network controls its own balance, chromatin structure and the biosynthesis of molecular cofactors; moreover, metabolic shifts are crucial in the response to oxidative stress and play a regulatory role in cancer.Evolution of the metabolic network and its structure Life probably began with the formation of compartmentalised autocatalytic chemical cycles. With the appearance of complex catalysts (ribonucleic acid-or protein-based enzymes), these cycles gained complexity, and evolved in their effectiveness and robustness [1]. These metabolic pathways now form the basis for life.As was the case for the first primitive life forms, the survival of today's complex organisms depends on the robustness and functionality of the metabolic framework [2]. To prevent and counteract perturbations in the flux, many biological control and sensor systems have evolved around the metabolic network. Metabolic pathways provide the cell with energy and supply macromolecular synthesis pathways with their required intermediates. They also balance metabolic systems under a variety of physiological conditions, and act as transducers and sensor systems for environmental conditions and stimuli. In addition, metabolic pathways are essential for crosstalk between metabolic regulatory components and the cellular transcriptome and proteome.As early as the 1960s, the principle that cells alter their gene expression in response to metabolic requirements has been known. The seminal work of Jacob and Monod, investigating the lac operon, uncovered one of the first examples of chemical-genetic regulation, by which bacterial cells adjust their enzyme production to the nutrient supply [3]. However, only recently have the broader implications of this principle emerged. Indeed, changes in the metabolic network not only control the metabolome, but they also have wide-ranging regulatory functions throughout biology.Most of the biochemical mechanisms that link the metabolic network to the transcriptome and proteome are incompletely understood. However, one type of regulation appears to be common: representative network intermediates bind to and modulate sensor function and activity of transcription factors, translational regulators, chromatin, enzymes, RNA molecules, and ion channels. Significant transcriptional changes around these intermediates identified them as reporter metabolites [4,5]. The use of intermediates as activity reporters ne...

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Section: Reviewmentioning

confidence: 99%

Regulatory crosstalk of the metabolic network

Grüning

Lehrach

Ralser

2010

Trends in Biochemical Sciences

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“…The M2 isoform, a splice variant of M1 is expressed during embryonic development (11) and tumor formation. It has been reported that tumor cells exclusively express PKM2 (10,12). In contrast to PKM1 that exists only as a highly active tetramer, PKM2 can shift between a tetrameric form that has a high affinity for its substrate PEP and a dimeric form with a low PEP affinity (12).…”

Section: Introductionmentioning

confidence: 99%

“…It has been reported that tumor cells exclusively express PKM2 (10,12). In contrast to PKM1 that exists only as a highly active tetramer, PKM2 can shift between a tetrameric form that has a high affinity for its substrate PEP and a dimeric form with a low PEP affinity (12). A high level of the dimeric form of PKM2 coincides with increased amounts of glycolytic phosphor-metabolites needed by biosynthetic processes.…”

Section: Introductionmentioning

confidence: 99%

“…Studies have shown that most PKM2 exists mainly as a dimeric form in tumor cells. Some viral oncoproteins like HPV-16E7 and pp60v-Src kinase (12,13) as well as cellular phosphotyrosine signaling (14,15) can induce the dimerization of PKM2, but the Ras oncogene induces the tetramerization of PKM2 (16,17). Recently, Kosugi et al (18) found that PKM2 activity is also regulated by direct binding of oncoprotein MUC1-C. Another important metabolic regulator of PKM2 is fructose 1,6-bisphosphate.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, Kosugi et al (18) found that PKM2 activity is also regulated by direct binding of oncoprotein MUC1-C. Another important metabolic regulator of PKM2 is fructose 1,6-bisphosphate. High level of this glycolytic intermediate reflects sufficient amounts of phosphor-metabolites and induces reassociation of the dimeric form of PKM2 to the highly active tetrameric form, thus shifting tumor metabolism from synthesis of cell building blocks to energy regeneration (12). So it is believed that PKM2 plays a key role in the channeling of glucose carbons either into catabolic or into anabolic pathways [14,15].…”

Section: Introductionmentioning

confidence: 99%

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Pyruvate kinase type M2 is upregulated in colorectal cancer and promotes proliferation and migration of colon cancer cells

Zhou

Sun

et al. 2012

IUBMB Life

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SummaryPyruvate kinase type M2 (PKM2) has been reported to be involved in aerobic glycolysis and cell growth in various tumors. However, the expression pattern of PKM2 in colorectal cancer (CRC) and the correlation between PKM2 expression and CRC remains unclear. The aim of this study is to investigate PKM2 expression and its possible role in CRC. We found that expression of PKM2 was increased in CRC and the increased PKM2 expression was associated with later stage and lymph metastasis of the tumors. Knockdown of PKM2 suppressed the aerobic glycolysis and decreased lactate production of colon cancer RKO cells. Knockdown of PKM2 repressed proliferation and migration of the cells. Inhibition of PKM2 suppressed xenograft tumor growth of RKO cells in vivo. These results suggest that the expression of PKM2 plays a critical role in development of CRC, and it may provide a growth advantage for colon cancer cells. Thus, PKM2 might be a potential therapeutic target for CRC.2012 IUBMB IUBMB Life, 64(9): 775-782, 2012

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FOXM1D potentiates PKM2‐mediated tumor glycolysis and angiogenesis

Zhang

Huang

et al. 2021

Molecular Oncology

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Tumor growth, especially in the late stage, requires adequate nutrients and rich vasculature, in which PKM2 plays a convergent role. It has been reported that PKM2, together with FOXM1D, is upregulated in late-stage colorectal cancer and associated with metastasis; however, their underlying mechanism for promoting tumor progression remains elusive. Herein, we revealed that FOXM1D potentiates PKM2-mediated glycolysis and angiogenesis through multiple protein-protein interactions. In the presence of FBP, FOXM1D binds to tetrameric PKM2 and assembles a heterooctamer, restraining PKM2 metabolic activity by about a half and thereby promoting aerobic glycolysis. Furthermore, FOXM1D interacts with PKM2 and NF-jB and induces their nuclear translocation with the assistance of the nuclear transporter importin 4. Once in the nucleus, PKM2 and NF-jB complexes subsequently augment VEGFA transcription. The increased VEGFA is secreted extracellularly via exosomes, an event potentiated by the interaction of FOXM1 with VPS11, eventually promoting tumor angiogenesis. Based on these findings, our study provides another insight into the role of PKM2 in the regulation of glycolysis and angiogenesis.

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Pyruvate kinase type M2 and its role in tumor growth and spreading

Cited by 707 publications

References 55 publications

Regulatory crosstalk of the metabolic network

Regulatory crosstalk of the metabolic network

Pyruvate kinase type M2 is upregulated in colorectal cancer and promotes proliferation and migration of colon cancer cells

FOXM1D potentiates PKM2‐mediated tumor glycolysis and angiogenesis

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