SAICAR Induces Protein Kinase Activity of PKM2 that Is Necessary for Sustained Proliferative Signaling of Cancer Cells

Keller, Kirstie E.; Doctor, Zainab M.; Dwyer, Zachary W.; Lee, Young‐Sam

doi:10.1016/j.molcel.2014.02.015

Cited by 143 publications

(176 citation statements)

References 33 publications

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“…5 Interestingly, the interaction exists in several cases, indicating that PKM2 may also play a role in regulating DNA damage signaling in the context of a transcriptional inactivated P53.…”

Section: Discussionmentioning

confidence: 99%

“…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 phosphorylations of stat3 at tyrosine 705 and histone H3 at threonine 11 respectively activate the transcriptions of MEK5 and endothelial growth factor (EGF)-stimulated cyclin D1, leading to increased tumor cell proliferation.…”

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confidence: 99%

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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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“…5 Interestingly, the interaction exists in several cases, indicating that PKM2 may also play a role in regulating DNA damage signaling in the context of a transcriptional inactivated P53.…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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“…The role of PKM2 as a pleiotropic protein kinase has been demonstrated by protein microarray experiments, which found that more than 100 human proteins, mostly protein kinases, are phosphorylated by PKM2. In particular, PKM2 phosphorylates and activates ERK1/2, and the sustained ERK1/2 activation mediated by PKM2 is instrumental for cell proliferation (Keller et al, 2014). PKM2 has also been shown to interact with Oct4 (also known as POU5F1) upon treatment with dichloroacetate, a pyruvate dehydrogenase kinase inhibitor that promotes mitochondrial oxidative phosphorylation (Morfouace et al, 2014).…”

Section: Non-metabolic Functions Of Pkm2mentioning

confidence: 99%

Pyruvate kinase M2 at a glance

Yang

2015

Journal of Cell Science

155

179

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Reprogrammed metabolism is a key feature of cancer cells. The pyruvate kinase M2 (PKM2) isoform, which is commonly upregulated in many human cancers, has been recently shown to play a crucial role in metabolism reprogramming, gene transcription and cell cycle progression. In this Cell Science at a glance article and accompanying poster, we provide a brief overview of recent advances in understanding the mechanisms underlying the regulation of PKM2 expression, enzymatic activity, metabolic functions and subcellular location. We highlight the instrumental role of the non-metabolic functions of PKM2 in tumorigenesis and evaluate the potential to target PKM2 for cancer treatment.

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“…Increased PK activity through small molecule activation of PKM2 also impairs tumor growth in mice (Anastasiou et al 2012). Furthermore, potential nonglycolytic functions of PKM2 have been proposed (Luo et al 2011;Yang et al 2011Yang et al , 2012aGao et al 2012;Lu 2012;Keller et al 2014) but are controversial (Hosios et al 2015). Despite numerous studies of PKM2 in cultured tumor cells, whether PKM2 is required for cell proliferation in vivo remains a topic of debate.…”

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confidence: 99%

Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma

et al. 2016

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Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of pyruvate kinase (PK), and PKM2 expression is closely linked to embryogenesis, tissue regeneration, and cancer. To interrogate the functional requirement for PKM2 during development and tissue homeostasis, we generated germline PKM2-null mice (Pkm2). Unexpectedly, despite being the primary isoform expressed in most wild-type adult tissues, we found that Pkm2 −/− mice are viable and fertile. Thus, PKM2 is not required for embryonic or postnatal development. Loss of PKM2 leads to compensatory expression of PKM1 in the tissues that normally express PKM2. Strikingly, PKM2 loss leads to spontaneous development of hepatocellular carcinoma (HCC) with high penetrance that is accompanied by progressive changes in systemic metabolism characterized by altered systemic glucose homeostasis, inflammation, and hepatic steatosis. Therefore, in addition to its role in cancer metabolism, PKM2 plays a role in controlling systemic metabolic homeostasis and inflammation, thereby preventing HCC by a non-cell-autonomous mechanism.

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SAICAR Induces Protein Kinase Activity of PKM2 that Is Necessary for Sustained Proliferative Signaling of Cancer Cells

Cited by 143 publications

References 33 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 at a glance

Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma

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