Regulation of Metastasis and Angiogenesis by Autotaxin

自分泌运动因子对转移和血管生成的调节

• 批准号: 7338795
• 负责人: david d roberts
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7338795
• 关键词: Regulation; Metastasis; Angiogenesis; Autotaxin

Since ATX has been identified as the major source of serum and plasma lysophospholipase D (LPLD) activity, we extended our interests to include ATX substrates and products. Our group recently found that epigenetic agents (trichostatin A and 5-aza-2'-deoxycytodine) switch the ATX product sphingosine-1-phosphate (S1P) from an inhibitor to a stimulator of motility. Quantitative PCR revealed that the S1P receptor associated with inhibition of motility (S1P2) was downregulated, while the receptors associated with stimulation of motility (S1P1 and S1P3) were upregulated by these two agents. The effect of trichostatin A was readily reversible confirming that it did not result in a mutational effect, and 5-aza-2'-deoxycytidine caused demethylation of a putative S1P1 promoter. This was the first demonstration that this family of receptors (EDG receptors) could be susceptible to epigenetic regulation.Regulation of ATX expression is poorly understood. We collaborated in a study that compared breast cancer cells transfected with CST6 (candidate tumor suppressor-6) to mock-transfected cells. Elevated expression of CST6, which is expressed in normal breast epithelial but downregulated in breast cancer cells, was found to down-regulate the expression of ATX. We also participated in a study of ATX-transfected fibroblasts, which found that the presence of ATX and its substrate lysophosphatidylcholine prevented conditional apoptosis in fibroblasts. Because ATX plays a major role in regulating serum levels of lysophosphatidic acid (LPA), there has been great interest in finding ATX inhibitors. Our group previously found that L-histidine acts as a non-competitive, but non-specific, inhibitor of the LPLD activity of ATX. We recently collaborated in a study demonstrating that carba analogs of cyclic phosphatidic acid are selective inhibitors of ATX.

由于ATX已被确定为血清和血浆溶物磷脂酶D（LPLD）活性的主要来源，因此我们扩展了我们的兴趣，以包括ATX底物和产品。我们的小组最近发现，表观遗传剂（Trichostatin A和5-Aza-2'-脱氧胞霉素）将ATX产物1-磷酸盐（S1P）从抑制剂转换为运动性刺激剂。定量PCR表明，与抑制运动性（S1P2）相关的S1P受体被下调，而与运动刺激相关的受体（S1P1和S1P3）被这两种药物上调。 trichostatin a的作用很容易被证实，证明它不会产生突变作用，而5-aza-2'-脱氧胞苷丁胺引起了推定的S1P1启动子的去甲基化。这是第一次证明，这种受体（EDG受体）可能容易受到表观遗传调节的影响。ATX表达的调节知之甚少。我们在一项研究中进行了合作，该研究比较了将CST6（候选肿瘤抑制剂-6）与模拟转染的细胞转染的乳腺癌细胞。发现CST6的表达升高，该表达在正常的乳腺上皮表达，但在乳腺癌细胞中下调，可下调ATX的表达。我们还参加了ATX转染的成纤维细胞的研究，该研究发现ATX及其底物溶物磷脂酰胆碱的存在阻止了成纤维细胞中的条件细胞凋亡。由于ATX在调节溶血磷脂酸（LPA）的血清水平方面起着重要作用，因此人们对寻找ATX抑制剂非常感兴趣。我们的小组以前发现，L-依赖丁是ATX LPLD活性的非竞争性但非特异性抑制剂。我们最近在一项研究中合作，表明环状磷脂酸的Carba类似物是ATX的选择性抑制剂。