Selective inhibition of phosphatidylinositol 3-kinase by phosphatidic acid and related lipids.
Activation of phosphatidylinositol 3-kinase (PI 3-kinase) is necessary for stimulation of cell division and inhibition of apoptosis in several cell types. We report that a synthetic phosphonolipid, 4-(hexadecyloxy)-3-(S)-methoxybutyl phosphonic acid (PoA), as well as the naturally occurring lipids, phosphatidic acid and lyso-phosphatidic acid, are potent and specific inhibitors of PI 3-kinase. The IC50's for inhibition using phosphatidylinositol as substrate ranged from 10-20 microM. PoA is also the putative primary intracellular metabolite following phospholipase D hydrolysis of the anti-tumour ether lipid, 2'-(trimethylammonio) ethyl-4-(hexadecyloxy)-3-(S)-methoxybutanephosphonate. These results suggests that inhibition of PI 3-kinase following metabolic degradation of ether lipids by phospholipase D may contribute to the cytotoxicity of these compounds. The sensitivity of PI 3-kinase to PA and lyso-PA could imply cross-talk between the phospholipase D and PI 3-kinase signal transduction pathways in vivo.
Lauener
R
R
Department of Medicine, University of British Columbia, Vancouver, Canada.
Shen
Y
Y
Duronio
V
V
Salari
H
H
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008246:Lysophospholipids / Q000494:pharmacology; D063065:Organophosphonates / Q000494:pharmacology; D010712:Phosphatidic Acids / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases; D010716:Phosphatidylinositols / Q000378:metabolism; D010743:Phospholipids / Q000494:pharmacology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011817:Rabbits
C095984:4-(hexadecyloxy)-3-methoxybutyl phosphonic acid; D004791:Enzyme Inhibitors; D008246:Lysophospholipids; D063065:Organophosphonates; D010712:Phosphatidic Acids; D010716:Phosphatidylinositols; D010743:Phospholipids; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor)