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.
|Number of pages||13|
|Publication status||Published - 15 Oct 2015|
Bibliographical noteDate of Acceptance: 17/10/2015
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Professor Jeremy M Tavare
- Life Sciences Faculty Office - Dean of Faculty of Life Sciences
- Fundamental Bioscience
- Dynamic Cell Biology
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Dr Emma E Vincent
- Bristol Medical School (THS) - Senior Lecturer in Molecular Metabolism
- School of Cellular and Molecular Medicine - Research Fellow
- Bristol Population Health Science Institute
Person: Academic , Academic , Member