Prolactin Inhibits Activity of Pyruvate Kinase M2 to Stimulate Cell Proliferation

Varghese, Bentley; Swaminathan, Gayathri; Plotnikov, A.N.; Tzimas, Christos; Yang, Ning; Rui, Hallgeir; Fuchs, Serge Y.

doi:10.1210/me.2010-0219

Cited by 23 publications

(18 citation statements)

References 47 publications

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“…In recent years, many small-molecule compounds have been found to specifically act on PKM2 without affecting other isozymes. They all inhibit cell proliferation to a certain extent [48][49][50]. However, both drugs that specifically target PKM2 and drugs that have been successfully applied in clinical practice are associated with the development of drug resistance, which is probably due to the nature of targeting a single site.…”

Section: Resultsmentioning

confidence: 99%

“…Hitosugi et al [26] have reported that expression of Y105F mutant PKM2 in lung cancer cell line H1299 prevents the tyrosine phosphorylation of this site, and PKM2 mainly exists in the tetramer form, leading to decreased tumorigenicity. It has recently been found that many small-molecule compounds and hormones target PKM2 and can inhibit cell proliferation [48][49][50].…”

Section: The Structural Features Of Pkm2mentioning

confidence: 99%

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Dual roles of PKM2 in cancer metabolism

Wu¹,

Han²

2013

ABBS

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Cancer cells have distinct metabolism that highly depends on glycolysis instead of mitochondrial oxidative phosphorylation alone, known as aerobic glycolysis. Pyruvate kinase (PK), which catalyzes the final step of glycolysis, has emerged as a potential regulator of this metabolic phenotype. Expression of PK type M2 (PKM2) is increased and facilitates lactate production in cancer cells, which determines whether the glucose carbons are degraded to pyruvate and lactate or are channeled into synthetic processes. Modulation of PKM2 catalytic activity also regulates the synthesis of DNA and lipids that are required for cell proliferation. However, the mechanisms by which PKM2 coordinates high-energy requirements with high anabolic activities to support cancer cell proliferation are still not completely understood. This review summarizes the biological characteristics of PKM2 and discusses the dual role in cancer metabolism as well as the potential therapeutic applications. Given its pleiotropic effects on cancer biology, PKM2 represents an attractive target for cancer therapy.

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Section: Resultsmentioning

confidence: 99%

Section: The Structural Features Of Pkm2mentioning

confidence: 99%

Dual roles of PKM2 in cancer metabolism

Wu¹,

Han²

2013

ABBS

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“…Human cancer cell lines engineered to express PKM1 produce less lactate than the same cells expressing PKM2 (Christofk et al 2008a). Also, PKM2 inhibition by prolactin increases lactate content and stimulates proliferation in human cell lines (Varghese et al 2010). One potential explanation for this paradox is that the overall increase in glycolytic flux results in higher flux through pyruvate kinase despite expression of the less active isoform.…”

Section: Pyruvate Kinase Influences the Fate Of Glucosementioning

confidence: 99%

Aerobic Glycolysis: Meeting the Metabolic Requirements of Cell Proliferation

Lunt

Heiden

2011

Annu. Rev. Cell Dev. Biol.

2,401

2,296

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Warburg's observation that cancer cells exhibit a high rate of glycolysis even in the presence of oxygen (aerobic glycolysis) sparked debate over the role of glycolysis in normal and cancer cells. Although it has been established that defects in mitochondrial respiration are not the cause of cancer or aerobic glycolysis, the advantages of enhanced glycolysis in cancer remain controversial. Many cells ranging from microbes to lymphocytes use aerobic glycolysis during rapid proliferation, which suggests it may play a fundamental role in supporting cell growth. Here, we review how glycolysis contributes to the metabolic processes of dividing cells. We provide a detailed accounting of the biosynthetic requirements to construct a new cell and illustrate the importance of glycolysis in providing carbons to generate biomass. We argue that the major function of aerobic glycolysis is to maintain high levels of glycolytic intermediates to support anabolic reactions in cells, thus providing an explanation for why increased glucose metabolism is selected for in proliferating cells throughout nature.

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“…Alternative splicing of a single exon from Pkm gives rise to either Pkm1 , which includes exon 9, or Pkm2 , where exon 9 replaces exon 10 (19). PKM1 is constitutively active and typically expressed in differentiated cells, while PKM2 has a regulated activity and is commonly expressed in cancer (20–24). PKM2 can be activated by fructose-1,6-bisphosphate, an upstream glycolytic intermediate (23,24) and inactivated by interaction with tyrosine-phosphorylated proteins responding to growth factor receptor signaling (20,21,25).…”

Section: Introductionmentioning

confidence: 99%

Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation

et al. 2017

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Aerobic glycolysis supports proliferation through unresolved mechanisms. We have previously shown that aerobic glycolysis is required for the regulated proliferation of cerebellar granule neuron progenitors (CGNPs), and for the growth of CGNP-derived medulloblastoma. Blocking the initiation of glycolysis via deletion of Hexokinase-2 (Hk2) disrupts CGNP proliferation and restricts medulloblastoma growth. Here, we assessed whether disrupting Pyruvate kinase-M (Pkm), an enzyme that acts in the terminal steps of glycolysis, would alter CGNP metabolism, proliferation and tumorigenesis. We observed a dichotomous pattern of PKM expression, in which post-mitotic neurons throughout the brain expressed the constitutively active PKM1 isoform, while neural progenitors and medulloblastomas exclusively expressed the less active PKM2. Isoform-specific Pkm2 deletion in CGNPs blocked all Pkm expression. Pkm2-deleted CGNPs showed reduced lactate production and increased SHH-driven proliferation. 13C-flux analysis showed that Pkm2 deletion reduced the flow of glucose carbons into lactate and glutamate without markedly increasing glucose-to-ribose flux. Pkm2 deletion accelerated tumor formation in medulloblastoma-prone ND2:SmoA1 mice, indicating the disrupting PKM releases CGNPs from a tumor-suppressive effect. These findings show that distal and proximal disruptions of glycolysis have opposite effects on proliferation, and that efforts to block the oncogenic effect of aerobic glycolysis must target reactions upstream of PKM.

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Prolactin Inhibits Activity of Pyruvate Kinase M2 to Stimulate Cell Proliferation

Cited by 23 publications

References 47 publications

Dual roles of PKM2 in cancer metabolism

Dual roles of PKM2 in cancer metabolism

Aerobic Glycolysis: Meeting the Metabolic Requirements of Cell Proliferation

Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation

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