Lauener R, Shen Y, Duronio V, Salari H
Department of Medicine, University of British Columbia, Vancouver, Canada.
Biochem Biophys Res Commun. 1995 Oct 4;215(1):8-14. doi: 10.1006/bbrc.1995.2427.
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.
磷脂酰肌醇3激酶（PI 3激酶）的激活对于多种细胞类型中细胞分裂的刺激和细胞凋亡的抑制是必需的。我们报告一种合成的膦脂，4-（十六烷氧基）-3-（S）-甲氧基丁基膦酸（PoA），以及天然存在的脂质磷脂酸和溶血磷脂酸，是PI 3激酶的强效特异性抑制剂。以磷脂酰肌醇作为底物时抑制作用的IC50范围为10 - 20微摩尔。PoA也是抗肿瘤醚脂质2'-（三甲基铵）乙基-4-（十六烷氧基）-3-（S）-甲氧基丁烷膦酸经磷脂酶D水解后的推定主要细胞内代谢物。这些结果表明，磷脂酶D对醚脂质进行代谢降解后对PI 3激酶的抑制作用可能有助于这些化合物的细胞毒性。PI 3激酶对PA和溶血PA的敏感性可能意味着体内磷脂酶D和PI 3激酶信号转导途径之间存在相互作用。
