The glycerol backbone of phospholipids derives from noncarbohydrate precursors in starved lung cancer cells

Proceedings of the National Academy of Sciences of the United States of America
Katharina LeithnerA Hrzenjak

Abstract

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 reduce...Continue Reading

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Citations

Aug 11, 2020·Molecular Oncology·Elisabeth SmolleKatharina Leithner
Feb 23, 2020·Frontiers in Genetics·Qifei WangYuan Chen
Apr 6, 2019·Current Molecular Medicine·Venu SeenappaKapaettu Satyamoorthy
Nov 21, 2018·Biomolecules·Alexander Triebl, Markus R Wenk
Nov 19, 2019·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Marc AragóJose C Perales
Nov 25, 2019·Biochimie·Mariana Lima-de-Freitas Marcondes-de-MelloValéria Ernestânia Chaves
Jan 8, 2021·Experimental & Molecular Medicine·Julia LeskoKatharina Leithner
Feb 6, 2021·International Journal of Molecular Sciences·Gabriele GrasmannKatharina Leithner
Feb 2, 2021·Journal of Diabetes and Metabolic Disorders·Lakshmipathi VadlakondaAramati B M Reddy
Jul 17, 2021·Annual Review of Nutrition·Melissa InigoShawn C Burgess

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Methods Mentioned

BETA
xenograft
FCS
xenografts
lipidation
PCR
transfection

Software Mentioned

Lipid Data Analyzer
SPSS
IsoCor

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