ATP citrate lyase inhibition can suppress tumor cell growth.
Many tumors display a high rate of glucose utilization, as evidenced by 18-F-2-deoxyglucose PET imaging. One potential advantage of catabolizing glucose through glycolysis at a rate that exceeds bioenergetic need is that the growing cell can redirect the excess glycolytic end product pyruvate toward lipid synthesis. Such de novo lipid synthesis is necessary for membrane production and lipid-based posttranslational modification of proteins. A key enzyme linking glucose metabolism to lipid synthesis is ATP citrate lyase (ACL), which catalyzes the conversion of citrate to cytosolic acetyl-CoA. ACL inhibition by RNAi or the chemical inhibitor SB-204990 limits in vitro proliferation and survival of tumor cells displaying aerobic glycolysis. The same treatments also reduce in vivo tumor growth and induce differentiation.
Hatzivassiliou
Georgia
G
Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Zhao
Fangping
F
Bauer
Daniel E
DE
Andreadis
Charalambos
C
Shaw
Anthony N
AN
Dhanak
Dashyant
D
Hingorani
Sunil R
SR
Tuveson
David A
DA
Thompson
Craig B
CB
D001275:ATP Citrate (pro-S)-Lyase / Q000037:antagonists & inhibitors*; D001483:Base Sequence; D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006706:Homeostasis; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D008928:Mitochondria / Q000502:physiology; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology*; D034741:RNA, Small Interfering / Q000502:physiology
D017931:DNA Primers; D004791:Enzyme Inhibitors; D007783:Lactones; D034741:RNA, Small Interfering; C112852:SB 204990; D001275:ATP Citrate (pro-S)-Lyase