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Evaluation of tumor M2-pyruvate kinase (Tumor M2-PK) as a biomarker for pancreatic cancer.

ABSTRACT: Expression of the dimeric M2 isoenzyme of pyruvate kinase, termed Tumor M2-PK, is increased in some human cancers. This study evaluates the potential role of pre-operative Tumor M2-PK as a marker of prognosis in patients with pancreatic malignancy.Seventy-three consecutive patients with a clinical diagnosis of pancreatic or peri-ampullary cancer were enrolled. Their median (range) age was 66 (23-83) years. Pre-operative samples of venous blood were taken for analysis of Tumor M2-PK. The full study protocol was approved by the North West Research Ethics Committee (protocol number 06/MRE08/69).The mean (standard deviation) plasma Tumor M2-PK in pancreatic/peri-ampullary malignancy was 60.3 (106.5) U/ml and 22 U/ml (SD: 12 U/ml) in benign disease (p ?27 U/mL), Ca19-9 (>?39 U/ml), resection status, and disease stage were associated with poorer survival. Tumor M2-PK values greater than 27 U/ml were associated with inferior survival compared to those with lower values (hazard ratio 2.049, significantly increased risk of death, p =?0.042).This preliminary study shows that an elevated level of Tumor M2-PK (with a cutoff threshold of 27 U/mL) measured pre-operatively is associated with poorer prognosis in patients with pancreatic and peri-ampullary cancer.

SUBMITTER: Bandara IA

PROVIDER: S-EPMC5853155 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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O-GlcNAcase targets pyruvate kinase M2 to regulate tumor growth.

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Tumor M2-PK: A novel urine marker of bladder cancer.

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| S-EPMC7052184 | biostudies-literature

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Lapachol inhibits glycolysis in cancer cells by targeting pyruvate kinase M2.

Project description:Reliance on aerobic glycolysis is one of the hallmarks of cancer. Although pyruvate kinase M2 (PKM2) is a key mediator of glycolysis in cancer cells, lack of selective agents that target PKM2 remains a challenge in exploiting metabolic pathways for cancer therapy. We report that unlike its structural analog shikonin, a known inhibitor of PKM2, lapachol failed to induce non-apoptotic cell death ferroxitosis in hypoxia. However, melanoma cells treated with lapachol showed a dose-dependent inhibition of glycolysis and a corresponding increase in oxygen consumption. Accordingly, in silico studies revealed a high affinity-binding pocket for lapachol on PKM2 structure. Lapachol inhibited PKM2 activity of purified enzyme as well as in melanoma cell extracts. Blockade of glycolysis by lapachol in melanoma cells led to decreased ATP levels and inhibition of cell proliferation. Furthermore, perturbation of glycolysis in melanoma cells with lapachol sensitized cells to mitochondrial protonophore and promoted apoptosis. These results present lapachol as an inhibitor of PKM2 to interrogate metabolic plasticity in tumor cells.

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Cancer-associated mutations in human pyruvate kinase M2 impair enzyme activity.

Project description:Mammalian pyruvate kinase catalyzes the final step of glycolysis, and its M2 isoform (PKM2) is widely expressed in proliferative tissues. Mutations in PKM2 are found in some human cancers; however, the effects of these mutations on enzyme activity and regulation are unknown. Here, we characterized five cancer-associated PKM2 mutations, occurring at various locations on the enzyme, with respect to substrate kinetics and activation by the allosteric activator fructose-1,6-bisphosphate (FBP). The mutants exhibit reduced maximal velocity, reduced substrate affinity, and/or altered activation by FBP. The kinetic parameters of five additional PKM2 mutants that have been used to study enzyme function or regulation also demonstrate the deleterious effects of mutations on PKM2 function. Our findings indicate that PKM2 is sensitive to many amino acid changes and support the hypothesis that decreased PKM2 activity is selected for in rapidly proliferating cells.

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