STAT3-independent inhibition of lysophosphatidic acid-mediated upregulation of connective tissue growth factor (CTGF) by cucurbitacin I
STAT3-independent inhibition of lysophosphatidic acid-mediated upregulation of connective tissue growth factor (CTGF) by cucurbitacin I
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DOI：
10.1016/j.bcp.2006.04.001
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发表时间：
2006-06-28
影响因子：
5.8
通讯作者：
Goppelt-Struebe, Margarete
中科院分区：
文献类型：
--
作者：
Graness, Angela;Poli, Valeria;Goppelt-Struebe, Margarete
葫芦素被认为是抗肿瘤药物，因为它们干扰STAT 3信号传导，但也可能影响肌动蛋白细胞骨架的完整性。在本研究中，葫芦素I的效果进行了研究，在成纤维细胞。在这些细胞中，葫芦素I干扰溶血磷脂酸（LPA）信号。它抑制粘着斑蛋白的酪氨酸磷酸化和结缔组织生长因子（CTGF）（一种有效的促纤维化蛋白）的诱导。用PP 2抑制Src家族激酶，而不是用无活性的类似物PP 3，也干扰了LPA介导的酪氨酸磷酸化和CTGF的诱导。Jak 2-STAT 3信号转导似乎是连接环节，因为CTGF诱导对AG 490（Jak 2的抑制剂）和葫芦素1（Jak 2和STAT 3的抑制剂）敏感。然而，LPA不激活STAT 3的酪氨酸磷酸化。此外，葫芦素I在STAT 3敲除细胞中与在对照细胞中一样有效。因此，葫芦素I的抑制作用与STAT 3的抑制无关。免疫细胞化学分析显示，葫芦素I处理的细胞F-肌动蛋白纤维解体，重组为F-肌动蛋白斑块，粘着斑消退。表型变化类似于用细胞松弛素D处理细胞后观察到的变化，细胞松弛素D已被证明干扰CTGF诱导。葫芦素I的浓度已被证明靶向Jak 2-STAT 3信号传导，因此，深刻地影响肌动蛋白细胞骨架。因此也可以在非肿瘤细胞中调节细胞形态、迁移、粘附和基因表达。(c)2006年爱思唯尔公司All rights reserved.
Cucurbitacins are recognised as anti-tumour agents because of their interference with STAT3 signalling, but may also affect the integrity of the actin cytoskeleton. In the present study the effect of cucurbitacin I was investigated in fibroblasts. In these cells, cucurbitacin I interfered with lysophosphatidic acid (LPA) signalling. It inhibited tyrosine phosphorylation of focal adhesion proteins and induction of connective tissue growth factor (CTGF), a potent profibrotic protein. Inhibition of Src family kinases with PP2, but not the inactive analogue PP3, also interfered with LPA-mediated tyrosine phosphorylation and induction of CTGF. Jak2-STAT3 signalling seemed to be the connecting link, because CTGF induction was sensitive to AG490, an inhibitor of Jak2, and cucurbitacin 1, an inhibitor of Jak2 and STAT3. However, LPA did not activate tyrosine phosphorylation of STAT3. Furthermore, cucurbitacin I was as effective in STAT3 knock out cells as in control cells. Therefore, the inhibitory effect of cucurbitacin I was not related to inhibition of STAT3.Immunocytochemical analysis of cucurbitacin I-treated cells revealed disassembly of F-actin fibres, reorganisation into F-actin patches and resolution of focal adhesions. The phenotypic changes resembled changes observed after treatment of the cells with cytochalasin D, which has been shown to interfere with CTGF induction. Concentrations of cucurbitacin I, which have been shown to target Jak2-STAT3 signalling, thus, profoundly affect the actin cytoskeleton. and may therefore modulate cell morphology, migration, adherence and gene expression also in non-tumour cells. (c) 2006 Elsevier Inc. All rights reserved.