Regulation of vascular endothelial growth factor expression by EMMPRIN via the PI3K-Akt signaling pathway
Regulation of vascular endothelial growth factor expression by EMMPRIN via the PI3K-Akt signaling pathway
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DOI：
10.1158/1541-7786.mcr-06-0042
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发表时间：
2006-06-01
影响因子：
5.2
通讯作者：
Yan, Li
中科院分区：
文献类型：
--
作者：
Tang, Yi;Nakada, Marian T.;Yan, Li
细胞外基质金属蛋白酶（MMP）诱导剂（EMMPRIN）是一种在许多实体瘤中过表达的细胞表面糖蛋白。除了刺激基质MMP表达的能力外，肿瘤相关EMMPRIN还诱导血管内皮生长因子（VEGF）表达。为了探索EMMPRIN使用的潜在信号通路，我们研究了磷酸肌醇3-激酶（PI 3 K）-Akt、丝裂原活化蛋白激酶（MAPK）、JUN和p38激酶在EMMPRIN介导的VEGF调节中的参与。EMMPRIN在MDA-MB-231乳腺癌细胞中的过表达仅刺激Akt和MAPK的磷酸化，而不刺激JUN和p38激酶的磷酸化。相反，EMMPRIN表达的抑制导致Akt和MAPK磷酸化的抑制。此外，PI 3 K特异性抑制剂LY 294002以剂量和时间依赖性方式抑制EMMPRIN过表达细胞产生VEGF。另一方面，MAPK抑制剂U 0126不影响VEGF的产生。在体内，EMMPRIN过表达的肿瘤与VEGF表达升高有高水平的Akt和MAPK磷酸化。最后，当用重组EMMPRIN处理成纤维细胞时，Akt激酶而不是MAPK被磷酸化，伴随着VEGF产生的增加。Akt激酶的激活和VEGF的诱导都被EMMPRIN的中和抗体特异性抑制。我们的研究结果表明，在肿瘤和成纤维细胞中，EMMPRIN通过PI 3 K-Akt途径调节VEGF的产生，而不是通过MAPK、JUN或38激酶途径。
Extracellular matrix metalloproteinase (MMP) inducer (EMMPRIN) is a cell surface glycoprotein overexpressed in many solid tumors. In addition to its ability to stimulate stromal MMP expression, tumor-associated EMMPRIN also induces vascular endothelial growth factor (VEGF) expression. To explore the underlying signaling pathways used by EMMPRIN, we studied the involvement of phosphoinositide 3-kinase (PI3K)-Akt, mitogen-activated protein kinase (MAPK), JUN, and p38 kinases in EMMPRIN-mediated VEGF regulation. Overexpression of EMMPRIN in MDA-MB-231 breast cancer cells stimulated the phosphorylation of only Akt and MAPKs but not that of JUN and p38 kinases. Conversely, inhibition of EMMPRIN expression resulted in suppressed Akt and MAPK phosphorylation. Furthermore, the PI3K-specific inhibitor LY294002 inhibited VEGF production by EMMPRIN-overexpressing cells in a dose- and time-dependent manner. On the other hand, the MAPK inhibitor U0126 did not affect VEGF production. In vivo, EMMPRIN-overexpressing tumors with elevated VEGF expression had a high level of phosphorylation of Akt and MAPK. Finally, when fibroblast cells were treated with recombinant EMMPRIN, Akt kinase but not MAPK was phosphorylated concomitant with an increase in VEGF production. Both the activation of Akt kinase and the induction of VEGF were specifically inhibited with a neutralizing antibody to EMMPRIN. Our results show that in both tumor and fibroblast cells EMMPRIN regulates VEGF production via the PI3K-Akt pathway but not via the MAPK, JUN, or 38 kinase pathways.