Current Status of Tumor M2 Pyruvate Kinase (Tumor M2-PK) as a Biomarker of Gastrointestinal Malignancy

Hathurusinghe, Harsha R; Goonetilleke, Kolitha; Siriwardena, Ajith K.

doi:10.1245/s10434-007-9481-x

Cited by 57 publications

(35 citation statements)

References 23 publications

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“…To explore the potential functions of nuclear PKM2 in response to etoposide treatment, we fractionated the nuclear extracts of etoposide-treated and untreated MCF7 cells by size-exclusion chromatography, followed by detection of PKM2 protein. The results demonstrated that, consistent with previous findings in most cancer cells (3,(21)(22)(23), nuclear PKM2 predominantly existed in low-molecular-weight fractions (fractions 41-45) corresponding to PKM2 dimer. Unexpectedly, an aliquot part of nuclear PKM2 also existed in a high-molecular-weight (Ͼ669 kDa) fractions (fractions 24 -28) (upper panel, Fig.…”

Section: Identification Of Nuclear Pkm2-interacting Proteins In Dnadasupporting

confidence: 91%

A Novel Role for Pyruvate Kinase M2 as a Corepressor for P53 during the DNA Damage Response in Human Tumor Cells

Wang

et al. 2016

Journal of Biological Chemistry

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Edited by Patrick SungThe pyruvate kinase (PK) is a rate-limiting glycolytic enzyme catalyzing the dephosphorylation of phosphoenolpyruvate to pyruvate, yielding one molecule of ATP. The M2 isoform of PK (PKM2) is predominantly expressed in normal proliferating cells and tumors, and both metabolic and non-metabolic activities for the enzyme in promoting tumor cell proliferation have been identified. However, the exact roles of PKM2 in tumor initiation, growth and maintenance are not yet fully understood. Using immunoprecipitation-coupled LC-MS/MS in MCF7 cells exposed to DNA-damaging agent, we report that the nuclear PKM2 interacts directly with P53 protein, a critical safeguard for genome stability. Specifically, PKM2 inhibits P53-dependent transactivation of the P21 gene by preventing P53 binding to the P21 promoter, leading to a nonstop G 1 phase. As a result, PKM2 expression provides a growth advantage for tumor cells in the presence of a DNA damage stimulus. In addition, PKM2 interferes with phosphorylation of P53 at serine 15, known to stimulate P53 activity by the ATM serine/threonine kinase. These findings reveal a new role for PKM2 in modulating the DNA damage response and illustrate a novel mechanism of PKM2 participating in tumorigenesis.Pyruvate kinase (PK), 4 a rate-limiting enzyme of glycolysis, catalyzes the transfer of phosphate from phosphoenolpyruvate (PEP) to ADP, yielding one molecule of ATP and pyruvate. The PK consists of four isoforms, the PKLR gene-encoded PKL and PKR isoforms and the PKM gene-encoded M1 (PKM1) and M2 (PKM2) isoforms, which express in different types of mammalian cells and tissues. PKM1 constitutively forms stable tetramers (the active form of PK) and is expressed in normal adult tissues that require high levels of energy, such as the heart, brain, and skeletal muscle. In contrast, PKM2 exists in either tetramers or dimers with less activity and metabolic intermediate fructose-1,6-bisphosphate (FBP) can allosterically activate PKM2 by promoting the formation of tetramer from dimer (1, 2). PKM2 is selectively expressed in normal proliferating cells as well as tumor cells, indicating an indispensable role in cancer development.There are two known mechanisms by which PKM2 favors tumor cell growth, one dependent on and one independent of glycolysis. As a glycolytic enzyme, PKM2 in tumor cells shifts glucose metabolism from oxidative phosphorylation to glycolysis under normoxic conditions, a phenomenon termed the Warburg effect or aerobic glycolysis (3). On the other hand, non-metabolic function of PKM2, which is mainly associated with the nuclear PKM2, has been identified as a major contributor during tumorigenesis. For example, nuclear PKM2 displays kinase activity in phosphorylating a number of protein substrates, including histone H3 (4, 5), signal transducer and activator of transcription 3 (stat3) (6, 7), Bub3 (8), and myosin light chain 2 (MLC2) (9), for which PKM2 uses the high-energy phosphate from PEP but not ATP as a phosphate donor. The PKM2-induced phosphorylation...

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Section: Identification Of Nuclear Pkm2-interacting Proteins In Dnadasupporting

confidence: 91%

A Novel Role for Pyruvate Kinase M2 as a Corepressor for P53 during the DNA Damage Response in Human Tumor Cells

Wang

et al. 2016

Journal of Biological Chemistry

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“…A very high percentage of cancer patients of different cancer types have elevated levels of PKM2 in their blood circulation (22). We show that the circulative PKM2 plays a critical role in facilitating tumor growth by promoting tumor angiogenesis.…”

Section: Discussionmentioning

confidence: 78%

Pyruvate Kinase M2 in Blood Circulation Facilitates Tumor Growth by Promoting Angiogenesis

Zhang

Qiao

et al. 2014

Journal of Biological Chemistry

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Background: It is known that PKM2 is present in cancer patient blood. It is not known if PKM2 functions in cancer progression. Results: PKM2 in blood facilitates tumor growth by promoting tumor angiogenesis via increasing angiogenic endothelial cell migration and ECM attachment. Conclusion: Extracellular PKM2 promotes tumor angiogenesis. Significance: We reveal a novel mechanism of cancer angiogenesis that could potentially be a new target for anti-angiogenesis.

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“…PKM2 expression was shown to be involved in early tumorigenesis (28) and can be detected in the blood and stool of cancer patients (9,82); furthermore, increases in PKM2 levels were reported to correlate with tumor size and stage (9). As described in another article in this CCR Focus section by Yang and colleagues, mutations of IDH1 and IDH2 are also reported to be easily detectable using small amounts of tumor samples (83).…”

Section: Discussionmentioning

confidence: 96%

Pyruvate Kinase M2: Multiple Faces for Conferring Benefits on Cancer Cells

Tamada

Suematsu

Saya

2012

Clinical Cancer Research

207

199

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The M2 splice isoform of pyruvate kinase (PKM2), an enzyme that catalyzes the later step of glycolysis, is a key regulator of aerobic glycolysis (known as the Warburg effect) in cancer cells. Expression and low enzymatic activity of PKM2 confer on cancer cells the glycolytic phenotype, which promotes rapid energy production and flow of glycolytic intermediates into collateral pathways to synthesize nucleic acids, amino acids, and lipids without the accumulation of reactive oxygen species. PKM2 enzymatic activity has also been shown to be negatively regulated by the interaction with CD44 adhesion molecule, which is a cell surface marker for cancer stem cells. In addition to the glycolytic functions, nonglycolytic functions of PKM2 in cancer cells are of particular interest. PKM2 is induced translocation into the nucleus, where it activates transcription of various genes by interacting with and phosphorylating specific nuclear proteins, endowing cancer cells with a survival and growth advantage. Therefore, inhibitors and activators of PKM2 are well underway to evaluate their anticancer effects and suitability for use as novel therapeutic strategies.

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Current Status of Tumor M2 Pyruvate Kinase (Tumor M2-PK) as a Biomarker of Gastrointestinal Malignancy

Cited by 57 publications

References 23 publications

A Novel Role for Pyruvate Kinase M2 as a Corepressor for P53 during the DNA Damage Response in Human Tumor Cells

A Novel Role for Pyruvate Kinase M2 as a Corepressor for P53 during the DNA Damage Response in Human Tumor Cells

Pyruvate Kinase M2 in Blood Circulation Facilitates Tumor Growth by Promoting Angiogenesis

Pyruvate Kinase M2: Multiple Faces for Conferring Benefits on Cancer Cells

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