The glycerol backbone of phospholipids derives from noncarbohydrate precursors in starved lung cancer cells
| Autor: | Alexandra Bertsch, Andrea Olschewski, Thomas Züllig, Elvira Stacher, Beatrix I. Wieser, Harald Köfeler, Andelko Hrzenjak, Ruth Prassl, Barbara Hinteregger, Alexander Triebl, Martin Trötzmüller, Petra Leko, Alessandro Valli, Gabriele Grasmann, Horst Olschewski, Adrian L. Harris, Katharina Leithner |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Glycerol
Male 0301 basic medicine Glutamine Mice Nude digestive system Mice 03 medical and health sciences Neoplasms PCK2 Glyceroneogenesis medicine Animals Humans Glycolysis Lactic Acid Phospholipids Multidisciplinary Chemistry Cancer Metabolism medicine.disease Glucose 030104 developmental biology Biochemistry Gluconeogenesis A549 Cells Cancer cell Heterografts Phosphoenolpyruvate carboxykinase Phosphoenolpyruvate Carboxykinase (ATP) |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 115(24) |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Cancer cells are reprogrammed to consume large amounts of glucose to support anabolic biosynthetic pathways. However, blood perfusion and consequently the supply with glucose are frequently inadequate in solid cancers. PEPCK-M (PCK2), the mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK), has been shown by us and others to be functionally expressed and to mediate gluconeogenesis, the reverse pathway of glycolysis, in different cancer cells. Serine and ribose synthesis have been identified as downstream pathways fed by PEPCK in cancer cells. Here, we report that PEPCK-M-dependent glycerol phosphate formation from noncarbohydrate precursors (glyceroneogenesis) occurs in starved lung cancer cells and supports de novo glycerophospholipid synthesis. Using stable isotope-labeled glutamine and lactate, we show that PEPCK-M generates phosphoenolpyruvate and 3-phosphoglycerate, which are at least partially converted to glycerol phosphate and incorporated into glycerophospholipids (GPL) under glucose and serum starvation. This pathway is required to maintain levels of GPL, especially phosphatidylethanolamine (PE), as shown by stable shRNA-mediated silencing of PEPCK-M in H23 lung cancer cells. PEPCK-M shRNA led to reduced colony formation after starvation, and the effect was partially reversed by the addition of dioleyl-PE. Furthermore, PEPCK-M silencing abrogated cancer growth in a lung cancer cell xenograft model. In conclusion, glycerol phosphate formation for de novo GPL synthesis via glyceroneogenesis is a newly characterized anabolic pathway in cancer cells mediated by PEPCK-M under conditions of severe nutrient deprivation. |
| Databáze: | OpenAIRE |
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