FGF-2 and TPA induce matrix metalloproteinase-9 secretion in MCF-7 cells through PKC activation of the Ras/ERK pathway
FGF-2 and TPA induce matrix metalloproteinase-9 secretion in MCF-7 cells through PKC activation of the Ras/ERK pathway
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DOI：
10.1016/s0006-291x(02)00350-9
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发表时间：
2002-05-17
影响因子：
3.1
通讯作者：
Ledoux, D
中科院分区：
文献类型：
--
作者：
Liu, JF;Crépin, M;Ledoux, D
基质金属蛋白酶（Matrix metalloproteinases, MMPs）在肿瘤转移中起重要作用。在这里。我们研究了成纤维细胞生长因子-2 （FGF-2）和12- o -十四烷酰基磷酸-13-乙酸酯（TPA）对乳腺癌MCF-7细胞分泌IV型胶原酶（MMP-2、MMP-9）的影响。明胶酶谱图显示，FGF-2和TPA均能刺激MCF-7细胞中MMP-9的分泌，而不改变MMP-2的分泌水平。信号级联研究表明，FGF-2和TPA均可诱导Ras活化。c-Raf磷酸化、丝裂原活化蛋白激酶/ERK激酶（MEK1,2）磷酸化和细胞外信号调节激酶（ERK1,2）磷酸化。瞬时转染具有显性阴性Ras （Ras- n17）的MCF-7细胞和MEK1/2抑制剂PD98059 A泛蛋白激酶C （PKC）抑制剂GF109203X可完全消除FGF-2和tpa诱导的MMP-9分泌和ERK1,2磷酸化，显著抑制FGF-2和tpa诱导的MMP-9分泌。此外，使用异构体特异性PKC抑制剂如Rotllerin和Go6976表明PKC-delta异构体可能是FGF-2和TPA营养信号通路的一个组成部分，这些结果表明FGF-2和TPA主要通过PKC依赖性激活Ras/ERK1/2信号通路诱导MCF-7细胞分泌MMP-9。(C) 2002 Elsevier Science （USA）。版权所有。
Matrix metalloproteinases (MMPs) play an important role in cancer metastasis. Here. we investigated the effect of fibroblast growth factor-2 (FGF-2) and 12-O-tetradecanoylphorbol-13-acetate (TPA) on the secretion of type IV collagenases (MMP-2, MMP-9) in breast cancer MCF-7 cells. As shown by gelatin zymography, both FGF-2 and TPA stimulated the secretion of MMP-9 in MCF-7 cells while they did not change the level of MMP-2 secretion. Signaling cascade studies indicated that both FGF-2 and TPA induced Ras activation. c-Raf phosphorylation, mitogen-activated protein kinase/ERK kinase (MEK1,2) phosphorylation, and extracellular signal-regulated kinase (ERK1,2) phosphorylation. The FGF-2- and TPA-induced MMP-9 secretion was significantly inhibited by transient transfection of MCF-7 cells with dominant negative Ras (Ras-N17) and by treatment with MEK1/2 inhibitor PD98059 A pan-protein kinase C (PKC) inhibitor, GF109203X, was found to totally abolish the FGF-2- and TPA-induced MMP-9 secretion and ERK1,2 phosphorylation. Use of isoform-specific PKC inhibitors such as Rotllerin and Go6976 Suggested, moreover, that the PKC-delta isoform is a likely component of FGF-2 and TPA trophic signaling, These results demonstrated that FGF-2 and TPA induce MMP-9 secretion in MCF-7 cells mainly through PKC-dependent activation of the Ras/ERK1/2 signaling pathway. (C) 2002 Elsevier Science (USA). All rights reserved.