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  • Title: Mitochondrial Phosphoenolpyruvate Carboxykinase Regulates Metabolic Adaptation and Enables Glucose-Independent Tumor Growth.
    Author: Vincent EE, Sergushichev A, Griss T, Gingras MC, Samborska B, Ntimbane T, Coelho PP, Blagih J, Raissi TC, Choinière L, Bridon G, Loginicheva E, Flynn BR, Thomas EC, Tavaré JM, Avizonis D, Pause A, Elder DJ, Artyomov MN, Jones RG.
    Journal: Mol Cell; 2015 Oct 15; 60(2):195-207. PubMed ID: 26474064.
    Abstract:
    Cancer cells adapt metabolically to proliferate under nutrient limitation. Here we used combined transcriptional-metabolomic network analysis to identify metabolic pathways that support glucose-independent tumor cell proliferation. We found that glucose deprivation stimulated re-wiring of the tricarboxylic acid (TCA) cycle and early steps of gluconeogenesis to promote glucose-independent cell proliferation. Glucose limitation promoted the production of phosphoenolpyruvate (PEP) from glutamine via the activity of mitochondrial PEP-carboxykinase (PCK2). Under these conditions, glutamine-derived PEP was used to fuel biosynthetic pathways normally sustained by glucose, including serine and purine biosynthesis. PCK2 expression was required to maintain tumor cell proliferation under limited-glucose conditions in vitro and tumor growth in vivo. Elevated PCK2 expression is observed in several human tumor types and enriched in tumor tissue from non-small-cell lung cancer (NSCLC) patients. Our results define a role for PCK2 in cancer cell metabolic reprogramming that promotes glucose-independent cell growth and metabolic stress resistance in human tumors.
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