The cytokine hepatocyte growth factor/scatter factor inhibits apoptosis and enhances DNA repair by a common mechanism involving signaling through phosphatidyl inositol 3′ kinase
The cytokine hepatocyte growth factor/scatter factor inhibits apoptosis and enhances DNA repair by a common mechanism involving signaling through phosphatidyl inositol 3′ kinase
复制标题
DOI：
10.1038/sj.onc.1203566
复制
发表时间：
2000-04-27
期刊：
影响因子：
8
通讯作者：
Rosen, EM
中科院分区：
文献类型：
--
作者：
Fan, SJ;Ma, YX;Rosen, EM
分散因子 (SF) [又名肝细胞生长因子 (HGF)]（称为 HGF/SF）是一种多功能细胞因子，可刺激肿瘤细胞侵袭和血管生成。我们最近报道，HGF/SF 可以保护上皮细胞和癌细胞免受 DNA 损伤剂的细胞毒性，并且 HGF/SF 介导的细胞保护与暴露于阿霉素的细胞中抗凋亡蛋白 Bcl-X-L 的上调有关。据报道，除了阻断细胞凋亡之外，HGF/SF 还显着增强了阿霉素或伽马辐射引起的 DNA 链断裂的修复。 MDA-MB-453 乳腺癌细胞中 Bcl-X-L 的组成型表达不仅模拟了 HGF/SF 介导的化疗耐药性，而且还增强了 DNA 链断裂的修复。HGF/SF 诱导化疗耐药性和 DNA 修复的能力被渥曼青霉素抑制，表明 HGF/SF 的这些活性部分归因于磷脂酰肌醇-3'-激酶 (PI3K) 依赖性信号传导途径。与这一发现一致的是，HGF/SF 诱导了 c-Akt（蛋白激酶-B）的磷酸化，c-Akt 是一种参与细胞凋亡抑制的 PI3K 底物；编码显性失活激酶失活 Akt 的表达载体部分但显着抑制 HGF/SF 介导的细胞保护和 DNA 修复。这些发现表明，HGF/SF 激活细胞存活和 DNA 修复途径；ay 涉及通过 PI3K 和 c-Akt 的信号传导以及 Bcl-X-L 表达的稳定，并且它们暗示 Bcl-X-L 参与 DNA 修复过程。
Scatter factor (SF) [aka, hepatocyte growth factor (HGF)] (designated HGF/SF) is a multifunctional cytokine that stimulates tumor cell invasion and angiogenesis. We recently reported that HGF/SF protects epithelial and carcinoma cells against cytotoxicity from DNA-damaging agents and that HGF/SF-mediated cytoprotection was associated with up-regulation of the anti-apoptotic protein Bcl-X-L in cells exposed to adriamycin, We now; report that in addition to blocking apoptosis, HGF/SF markedly enhances the repair of DNA strand breaks caused by adriamycin or gamma radiation. Constitutive expression of Bcl-X-L in MDA-MB-453 breast cancer cells not only simulated the HGF/SF-mediated chemoradioresistance, but also enhanced the repair of DNA strand breaks, The ability of HGF/SF to induce both chemoresistance and DNA repair was inhibited by wortmannin, suggesting that these activities of HGF/SF are due, in part, to a phosphatidylinositol-3'-kinase (PI3K) dependent signaling pathway. Consistent with this finding, HGF/SF induced the phosphorylation of c-Akt (protein kinase-B), a PI3K substrate implicated in apoptosis inhibition; and an expression vector encoding a dominant negative kinase inactive Akt partially but significantly inhibited HGF/SF-mediated cell protection and DNA repair. These findings suggest that HGF/SF activates a cell survival and DNA repair pathway;ay that involves signaling through PI3K and c-Akt and stabilization of the expression of Bcl-X-L and they implicate Bcl-X-L in the DNA repair process.