Phosphatidylcholine-derived phosphatidic acid and diacylglycerol are involved in the signaling pathways activated by docetaxel.

摘要: Taxanes are known to activate several cellular signals including mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-kappa B), tyrosine phosphorylation of Shc, serine Bcl-2. However, the mediators these signaling pathways unknown. Using U937 leukemic cells, we evaluated effect docetaxel on phosphatidylcholine (PC) its metabolites, phosphatidic acid (PA) diacylglycerol (DAG), their impact MAPK NF-kappa activation, as well Raf-1 Bcl-2 phosphorylation. Metabolic labeling studies showed that (10 nM) induced two waves PA production (130-140%), which were detected at 1 10 min. Docetaxel also stimulated DAG (130%), followed first wave. The initial burst was due phospholipase D (PLD)-mediated PC hydrolysis. Subsequent inhibited by phosphatidate phosphohydrolase (PAP) inhibitor, propranolol. R59949, a increased accumulation blocked second These results suggest triggers metabolic cascade consisting in PLD-mediated hydrolysis, release, PAP-dependent production, stimulation, leading conversion back PA. Neither R59949 nor propranolol influenced docetaxel-induced Raf-1/ERK activation. abrogated both activation phosphorylation, suggesting and/or DAG-derived contribute regulating events.