Mitochondrial Phosphoenolpyruvate Carboxykinase Regulates Metabolic Adaptation and Enables Glucose-Independent Tumor Growth

作者：Vincent Emma E; Sergushichev Alexey; Griss Takla; Gingras Marie Claude; Samborska Bozena; Ntimbane Thierry; Coelho Paula P; Blagih Julianna; Raissi Thomas C; Choiniere Luc; Bridon Gaelle; Loginicheva Ekaterina; Flynn Breanna R; Thomas Elaine C; Tavare Jeremy M; Avizonis Daina; Pause Arnim; Elder Douglas J E; Artyomov Maxim N; Jones Russell G

来源：Molecular Cell, 2015, 60(2): 195-207.

DOI：10.1016/j.molcel.2015.08.013

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.

• 出版日期2015-10-15