ATP citrate lyase is an important component of cell growth and transformation.
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 PI 3 K/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.
Bauer
Daniel E
DE
Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Hatzivassiliou
Georgia
G
Zhao
Fangping
F
Andreadis
Charalambos
C
Thompson
Craig B
CB
D001275:ATP Citrate (pro-S)-Lyase / Q000502:physiology*; D000595:Amino Acid Sequence; D002455:Cell Division / Q000502:physiology*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D005434:Flow Cytometry; D008969:Molecular Sequence Data
D001275:ATP Citrate (pro-S)-Lyase