Signal Transduction Research Group, Department of Biochemistry, School of Molecular and Systems Medicine, University of Alberta, Edmonton, T6G 2S2 Alberta, Canada.
Biochimie. 2011 Jan;93(1):61-70. doi: 10.1016/j.biochi.2010.08.002. Epub 2010 Aug 13.
Evidence from clinical, animal and cell culture studies demonstrates that increased autotaxin (ATX) expression is responsible for enhancing tumor progression, cell migration, metastases, angiogenesis and chemo-resistance. These effects depend mainly on the rapid formation of lysophosphatidate (LPA) by ATX. Circulating LPA has a half-life of about 3 min in mice and it is degraded by the ecto-activities of lipid phosphate phosphatases (LPPs). These enzymes also hydrolyze extracellular sphingosine 1-phosphate (S1P), a potent signal for cell division, survival and angiogenesis. Many aggressive tumor cells express high ATX levels and low LPP activities. This favors the formation of locally high LPA and S1P concentrations. Furthermore, LPPs attenuate signaling downstream of the activation of G-protein coupled receptors and receptor tyrosine kinases. Therefore, we propose that the low expression of LPPs in many tumor cells makes them hypersensitive to growth promoting and survival signals that are provided by LPA, S1P, platelet-derived growth factor (PDGF) and epidermal growth factor (EGF). One of the key signaling pathways in this respect appears to be activation of phospholipase D (PLD) and phosphatidate (PA) production. This is required for the transactivations of the EGFR and PDGFR and also for LPA-induced cell migration. PA also increases the activities of ERK, mTOR, myc and sphingosine kinase-1 (SK-1), which provide individual signals for cells division, survival, chemo-resistance and angiogenesis. This review focuses on the balance of signaling by bioactive lipids including LPA, phosphatidylinositol 3,4,5-trisphosphate, PA and S1P versus the action of ceramides. We will discuss how these lipid mediators interact to produce an aggressive neoplastic phenotype.
临床、动物和细胞培养研究证据表明，增加自分泌酶（ATX）的表达是增强肿瘤进展、细胞迁移、转移、血管生成和化疗耐药的原因。这些作用主要取决于 ATX 快速形成溶血磷脂酸（LPA）。循环中的 LPA 在小鼠中的半衰期约为 3 分钟，它被脂质磷酸酶（LPPs）的外切酶活性降解。这些酶还水解细胞外的鞘氨醇 1-磷酸（S1P），这是细胞分裂、存活和血管生成的有效信号。许多侵袭性肿瘤细胞表达高水平的 ATX 和低水平的 LPP 活性。这有利于局部形成高浓度的 LPA 和 S1P。此外，LPPs 减弱了 G 蛋白偶联受体和受体酪氨酸激酶激活后的信号转导。因此，我们提出，许多肿瘤细胞中 LPP 的低表达使它们对 LPA、S1P、血小板衍生生长因子（PDGF）和表皮生长因子（EGF）提供的促生长和存活信号过度敏感。在这方面，一个关键的信号通路似乎是磷脂酶 D（PLD）和磷酸酯（PA）的激活。这是 EGFR 和 PDGFR 的转激活以及 LPA 诱导的细胞迁移所必需的。PA 还增加 ERK、mTOR、myc 和鞘氨醇激酶-1（SK-1）的活性，这些信号分别为细胞分裂、存活、化疗耐药和血管生成提供信号。这篇综述重点介绍了包括 LPA、磷脂酰肌醇 3,4,5-三磷酸、PA 和 S1P 在内的生物活性脂质的信号平衡，以及神经酰胺的作用。我们将讨论这些脂质介质如何相互作用产生侵袭性肿瘤表型。
