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

Zhou, Chixing; Li, Xuebing; Sun, Heng; Zhang, Bo; Han, Ying; Jiang, Yi; Zhuang, Qiulin; Fang, Jing; Wu, Guohao

doi:10.1002/iub.1066

Cited by 92 publications

(83 citation statements)

References 45 publications

(65 reference statements)

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“…Zhou et al (Zhou et al, 2012) (Anastasiou et al, 2012;Christofk et al, 2008a). Our analysis of extracellular flux in real-time uncovered an enhanced glycolytic activity and a lower OXPHOS capacity for KD cells, which is in accordance with a rerouting of carbohydrates toward lactate instead of TCA cycle.…”

Section: Discussionsupporting

confidence: 67%

“…Previous studies have linked energy metabolism to colon cancer progression, and as a rate-limiting enzyme of glycolysis, PKM2 has been investigated Lunt et al, 2015;Yang et al, 2014;Zhou et al, 2012). Zhou et al (Zhou et al, 2012) (Anastasiou et al, 2012;Christofk et al, 2008a).…”

Section: Discussionmentioning

confidence: 99%

“…This process provides cancer cells with energy and precursors for the synthesis of nucleic acids, amino acids, and lipids to support cell division. Recent data indicate that overexpression of PKM2 in colon tumors connote poor outcome, as it is associated with advanced tumor stage and lymph node metastasis, and is essential for the aerobic MOL #106161 8 glycolysis of colon cancer cells in vitro (Cui and Shi, 2015;Yang et al, 2014;Yang et al, 2015;Zhou et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cross-Talk between Alternatively Spliced UGT1A Isoforms and Colon Cancer Cell Metabolism

Audet-Delage

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et al. 2017

Mol Pharmacol

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“…We selected the cell line HCT-116 for this study because it is known to overexpress M2PYK (30). Addition of 5 mM Phe or 20 μM T3 to the cell culture media significantly increased cell proliferation compared with vehicle treated cells, whereas addition of 1 mM F16BP resulted in complete inhibition of cell growth (Fig.…”

Section: Allosteric Inhibitor Phenylalanine Locks the M2pyk Tetramer mentioning

confidence: 99%

M2 pyruvate kinase provides a mechanism for nutrient sensing and regulation of cell proliferation

Morgan¹,

O’Reilly²,

Wear³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

153

247

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We show that the M2 isoform of pyruvate kinase (M2PYK) exists in equilibrium between monomers and tetramers regulated by allosteric binding of naturally occurring small-molecule metabolites. Phenylalanine stabilizes an inactive T-state tetrameric conformer and inhibits M2PYK with an IC 50 value of 0.24 mM, whereas thyroid hormone (triiodo-L-thyronine, T3) stabilizes an inactive monomeric form of M2PYK with an IC 50 of 78 nM. The allosteric activator fructose-1,6-bisphosphate [F16BP, AC 50 (concentration that gives 50% activation) of 7 μM] shifts the equilibrium to the tetrameric active Rstate, which has a similar activity to that of the constitutively fully active isoform M1PYK. Proliferation assays using HCT-116 cells showed that addition of inhibitors phenylalanine and T3 both increased cell proliferation, whereas addition of the activator F16BP reduced proliferation. F16BP abrogates the inhibitory effect of both phenylalanine and T3, highlighting a dominant role of M2PYK allosteric activation in the regulation of cancer proliferation. X-ray structures show constitutively fully active M1PYK and F16BP-bound M2PYK in an R-state conformation with a lysine at the dimer-interface acting as a peg in a hole, locking the active tetramer conformation. Binding of phenylalanine in an allosteric pocket induces a 13°rotation of the protomers, destroying the peg-in-hole R-state interface. This distinct T-state tetramer is stabilized by flipped out Trp/Arg side chains that stack across the dimer interface. Xray structures and biophysical binding data of M2PYK complexes explain how, at a molecular level, fluctuations in concentrations of amino acids, thyroid hormone, and glucose metabolites switch M2PYK on and off to provide the cell with a nutrient sensing and growth signaling mechanism.allosteric regulation | nutrient sensor | thyroid hormone T3 | Warburg effect T he last of 10 enzymatic steps used to convert glucose to pyruvate is carried out by pyruvate kinase (PYK), which transfers a phosphate from phosphoenolpyruvate to ADP to generate ATP. There are four human PYK isoforms (1); RPYK is restricted to erythrocytes, LPYK is found predominantly in liver and kidney, M1PYK is in muscle and brain, and M2PYK is found in fetal tissues and in proliferating cells. All four isoforms are active as tetramers; M1PYK is constitutively fully active, whereas R-, L-, and M2PYKs are activated by the effector molecule fructose-1,6-bisphosphate (F16BP) (2). M2PYK is a splice variant of the nonallosteric M1PYK isoform and differs by 22 amino acid residues (3). Recent quantification of the concentrations of constitutively fully active M1PYK and allosterically regulated M2PYK isoforms in both cancerous and control tissue samples has revealed that M2PYK is almost always the most abundant isoform in cancer cells, although it can also be predominant in matched control tissues (4). The up-regulation of the M2PYK isoform plays a key role in cancer metabolism (3) and explains the Warburg effect, in which proliferating cancer cells metabolize increas...

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“…Knocking-down of PKM2 suppressed the proliferation and migration of colon cancer RKO cells. 57 Lactate dehydrogenase (LDH) is a key metabolic enzyme catalyzing the transition of pyruvate to lactate. There are two types of subunits of LDH, designated M (muscle-type; LDHA gene product) and H (heart-type; LDHB gene product).…”

Section: How Does the Glycolysis Pathway Affect Tumor Cell Migration mentioning

confidence: 99%

How does cancer cell metabolism affect tumor migration and invasion?

Han¹,

Kang

Ji³

et al. 2013

Cell Adhesion & Migration

179

145

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

Cited by 92 publications

References 45 publications

Cross-Talk between Alternatively Spliced UGT1A Isoforms and Colon Cancer Cell Metabolism

Cross-Talk between Alternatively Spliced UGT1A Isoforms and Colon Cancer Cell Metabolism

M2 pyruvate kinase provides a mechanism for nutrient sensing and regulation of cell proliferation

How does cancer cell metabolism affect tumor migration and invasion?

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