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ATP citrate lyase is an important component of cell growth and transformation

Abstract

Cell proliferation requires a constant supply of lipids and lipid precursors to fuel membrane biogenesis and protein modification. Cytokine stimulation of hematopoietic cells directly stimulates glucose utilization in excess of bioenergetic demand, resulting in a shift from oxidative to glycolytic metabolism. A potential benefit of this form of metabolism is the channeling of glucose into biosynthetic pathways. Here we report that glucose supports de novo lipid synthesis in growing hematopoietic cells in a manner regulated by cytokine availability and the PI3K/Akt signaling pathway. The net conversion of glucose to lipid is dependent on the ability of cells to produce cytosolic acetyl CoA from mitochondria-derived citrate through the action of ATP citrate lyase (ACL). Stable knockdown of ACL leads to a significant impairment of glucose-dependent lipid synthesis and an elevation of mitochondrial membrane potential. Cells with ACL knockdown display decreased cytokine-stimulated cell proliferation. In contrast, these cells resist cell death induced by either cytokine or glucose withdrawal. However, ACL knockdown significantly impairs Akt-mediated tumorigenesis in vivo. These data suggest that enzymes involved in the conversion of glucose to lipid may be targets for the treatment of pathologic cell growth.

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Acknowledgements

We thank Debra Cromley for excellent technical assistance and Jeffrey Billheimer and Jane Glick for helpful discussions. Members of the Thompson laboratory, especially Monica Buzzai, Ralph DeBerardinis, Aimee Edinger, Casey Fox, and Peter Hammerman, provided valuable feedback. GH is a Damon Runyon Fellow supported by the Damon Runyon Cancer Research Foundation (DRG-#1714-02).

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Correspondence to Craig B Thompson.

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Bauer, D., Hatzivassiliou, G., Zhao, F. et al. ATP citrate lyase is an important component of cell growth and transformation. Oncogene 24, 6314–6322 (2005). https://doi.org/10.1038/sj.onc.1208773

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  • DOI: https://doi.org/10.1038/sj.onc.1208773

Keywords

  • ATP citrate lyase
  • Akt
  • glucose metabolism
  • lipid synthesis
  • cell growth
  • transformation

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