Tang Yi, Nakada Marian T, Rafferty Patricia, Laraio Jenny, McCabe Francis L, Millar Hillary, Cunningham Mark, Snyder Linda A, Bugelski Peter, Yan Li
Oncology Research, Centocor R&D, Inc., Malvern, Pennsylvania 19355, USA.
Mol Cancer Res. 2006 Jun;4(6):371-7. doi: 10.1158/1541-7786.MCR-06-0042.
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 p38 kinase pathways.
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。除了能够刺激基质MMP表达外，肿瘤相关的EMMPRIN还能诱导血管内皮生长因子（VEGF）表达。为了探究EMMPRIN所使用的潜在信号通路，我们研究了磷酸肌醇3激酶（PI3K）-Akt、丝裂原活化蛋白激酶（MAPK）、JUN和p38激酶在EMMPRIN介导的VEGF调节中的作用。EMMPRIN在MDA-MB-231乳腺癌细胞中的过表达仅刺激了Akt和MAPK的磷酸化，而未刺激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，PI3K特异性抑制剂LY294002以剂量和时间依赖性方式抑制了EMMPRIN过表达细胞的VEGF产生。另一方面，MAPK抑制剂U0126不影响VEGF产生。在体内，VEGF表达升高的EMMPRIN过表达肿瘤具有高水平的Akt和MAPK磷酸化。最后，当用重组EMMPRIN处理成纤维细胞时，Akt激酶而非MAPK被磷酸化，同时VEGF产生增加。用抗EMMPRIN的中和抗体特异性抑制了Akt激酶的激活和VEGF的诱导。我们的结果表明在肿瘤细胞和成纤维细胞中，EMMPRIN均通过PI3K-Akt途径而非MAPK、JUN或p38激酶途径调节VEGF产生。
