title: Association of C-terminal region of phosphoglycerate mutase with glycolytic complex regulates energy production in cancer cells.
abstract: Cancer cells prefer anaerobic ATP synthesis, regardless of the availability of oxygen. It has been hypothesized that in these cells, glycolytic enzymes associate into a large complex, which results in an increased efficiency of glycolytic flux. However, there is no convincing in vivo evidence supporting this hypothesis. Here, we show that all the enzymes of triose phosphate metabolism, from aldolase to pyruvate kinase consecutively, form a macromolecular complex in vivo and that disruption of such complex significantly inhibits lactate release and ATP synthesis in the glycolytic pathway. Composition of the complex and the effectiveness of the glycolytic flux depends on lactate and glucose concentration. High concentrations of exogenous lactate reduces association of the C-terminal region phosphoglycerate mutase (PGAM) with the complex which results in its disruption and inhibition of ATP synthesis. Additionally, high lactate affects nuclear localization of PGAM and ceases cell proliferation. Our findings might provide new prospects for cancer treatment using low-molecular weight competitors to destabilize the glycolytic complex and reduce proliferative potential of cancer cells.
authors.affiliation: Department of Animal Molecular Physiology, Wroclaw University, Wroclaw, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Kowalski
authors.forename: Dominika
authors.initials: D
authors.lastname: Nocon
authors.forename: Andrzej
authors.initials: A
authors.lastname: Gamian
authors.forename: Jerzy
authors.initials: J
authors.lastname: Kołodziej
authors.forename: Dariusz
authors.initials: D
authors.lastname: Rakus
mesh_terms: D021581:Active Transport, Cell Nucleus; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004734:Energy Metabolism / Q000187:drug effects; D005634:Fructose-Bisphosphate Aldolase / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D009097:Multienzyme Complexes; D010455:Peptides / Q000494:pharmacology; D010736:Phosphoglycerate Mutase / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011770:Pyruvate Kinase / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D009097:Multienzyme Complexes; D010455:Peptides; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D011770:Pyruvate Kinase; D005634:Fructose-Bisphosphate Aldolase; D010736:Phosphoglycerate Mutase; D005947:Glucose