Samadi N, Gaetano C, Goping I S, Brindley D N
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
Oncogene. 2009 Feb 19;28(7):1028-39. doi: 10.1038/onc.2008.442. Epub 2008 Dec 15.
Autotaxin (ATX) promotes cancer cell survival, growth, migration, invasion and metastasis. ATX converts extracellular lysophosphatidylcholine (LPC) into lysophosphatidate (LPA). As these lipids have been reported to affect cell signaling through their own G-protein-coupled receptors, ATX could modify the balance of this signaling. Also, ATX affects cell adhesion independently of its catalytic activity. We investigated the interactions of ATX, LPC and LPA on the apoptotic effects of Taxol, which is commonly used in breast cancer treatment. LPC had no significant effect on Taxol-induced apoptosis in MCF-7 breast cancer cells, which do not secrete significant ATX. Addition of incubation medium from MDA-MB-435 melanoma cells, which secrete ATX, or recombinat ATX enabled LPC to inhibit Taxol-induced apoptosis of MCF-7 cells. Inhibiting ATX activity blocked this protection against apoptosis. We conclude that LPC has no significant effect in protecting MCF-7 cells against Taxol treatment unless it is converted to LPA by ATX. LPA strongly antagonized Taxol-induced apoptosis through stimulating phosphatidylinositol 3-kinase and inhibiting ceramide formation. LPA also partially reversed the Taxol-induced arrest in the G2/M phase of the cell cycle. Our results support the hypothesis that therapeutic inhibition of ATX activity could improve the efficacy of Taxol as a chemotherapeutic agent for cancer treatment.
自分泌运动因子（ATX）可促进癌细胞的存活、生长、迁移、侵袭和转移。ATX可将细胞外溶血磷脂酰胆碱（LPC）转化为溶血磷脂酸（LPA）。由于据报道这些脂质可通过自身的G蛋白偶联受体影响细胞信号传导，因此ATX可能会改变这种信号传导的平衡。此外，ATX可独立于其催化活性影响细胞黏附。我们研究了ATX、LPC和LPA对紫杉醇凋亡效应的相互作用，紫杉醇常用于乳腺癌治疗。LPC对MCF-7乳腺癌细胞中紫杉醇诱导的凋亡无显著影响，该细胞系不分泌大量ATX。添加来自分泌ATX的MDA-MB-435黑色素瘤细胞的孵育培养基或重组ATX，可使LPC抑制MCF-7细胞中紫杉醇诱导的凋亡。抑制ATX活性可阻断这种对凋亡的保护作用。我们得出结论，除非LPC被ATX转化为LPA，否则它对保护MCF-7细胞免受紫杉醇处理无显著作用。LPA通过刺激磷脂酰肌醇3激酶并抑制神经酰胺形成，强烈拮抗紫杉醇诱导的凋亡。LPA还部分逆转了紫杉醇诱导的细胞周期G2/M期阻滞。我们的结果支持以下假设：治疗性抑制ATX活性可提高紫杉醇作为癌症治疗化疗药物的疗效。
