c-Src regulates constitutive and EGF-mediated VEGF expression in pancreatic tumor cells through activation of phosphatidyl inositol-3 kinase and p38 MAPK
c-Src regulates constitutive and EGF-mediated VEGF expression in pancreatic tumor cells through activation of phosphatidyl inositol-3 kinase and p38 MAPK
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DOI：
10.1097/01.mpa.0000178280.50534.0c
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发表时间：
2005-10-01
期刊：
影响因子：
2.9
通讯作者：
Gallick, GE
中科院分区：
文献类型：
--
作者：
Summy, JM;Trevino, JG;Gallick, GE
目的：多种信号蛋白可能在胰腺肿瘤中异常激活和/或过表达，包括非受体蛋白酪氨酸激酶Src。本研究的目的是确定Src在调节胰腺癌细胞株VEGF表达和血管生成潜能中的作用。方法：使用Src家族激酶选择性抑制剂PP 2抑制Src活性，并通过siRNA下调c-Src表达。通过选择性抑制剂破坏下游信号分子磷脂酰肌醇3 '-激酶（PI 3 K）和p38丝裂原活化蛋白激酶（MAPK）的活性。在体内血管生成进行了评估，通过使用凝胶泡沫assay.Results：Src活性或表达的抑制降低组成和EGF诱导的VEGF的生产。PI 3 K/Akt和p38 MAPK通路均以Src家族激酶依赖的方式对EGF-R活化进行活化，并且对于胰腺癌细胞中EGF介导的VEGF产生是重要的。此外，从Src抑制L3.6pl细胞的媒体未能促进血管生成到皮下植入到小鼠的凝胶泡沫，而从控制细胞的媒体促进强大的血管生成response.Conclusions：Src活性有助于组成和EGF诱导的VEGF表达和血管生成潜力的胰腺癌细胞。因此，Src可能是胰腺癌抗血管生成治疗的一个可行靶点。
Objectives: Multiple signaling proteins may be aberrantly activated and/or overexpressed in pancreatic tumors, including the nonreceptor protein tyrosine kinase Src. The goal of this study was to determine the role of Src in regulating VEGF expression and angiogenic potential in pancreatic cancer cell lines.Methods: Src activity was inhibited using the Src family kinase selective inhibitor PP2, and c-Src expression was down-regulated via siRNA. The activities of downstream signaling molecules phosphatidyl inositol 3'-kinase (PI3K) and p38 mitogen-activated protein kinase ( MAPK) were disrupted via selective inhibitors. In vivo angiogenesis was assessed through the use of a gel-foam assay.Results: Inhibition of Src activity or expression decreases both constitutive and EGF-induced VEGF production. Both the PI3K/Akt and p38 MAPK pathways are activated in a Src family kinase-dependent fashion on EGF-R activation and are important for EGF-mediated VEGF production in pancreatic cancer cells. Additionally, media from Src-inhibited L3.6pl cells fail to promote angiogenesis into gel foams implanted subcutaneously into mice, whereas media from control cells promote a robust angiogenic response.Conclusions: Src activity contributes to constitutive and EGF-induced VEGF expression and angiogenic potential in pancreatic cancer cells. Therefore, Src may be a viable target for antiangiogenesis therapy in pancreatic cancer.