Scatter factor/hepatocyte growth factor protects against cytotoxic death in human glioblastoma via phosphatidylinositol 3-kinase- and AKT-dependent pathways.
Scatter factor/hepatocyte growth factor protects against cytotoxic death in human glioblastoma via phosphatidylinositol 3-kinase- and AKT-dependent pathways.
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发表时间：
2000-08
期刊：
影响因子：
11.2
通讯作者：
Daniel C. Bowers;Saijun Fan;Kevin A. Walter;R. Abounader;Jeffery A. Williams;E. Rosen;J. Laterra
中科院分区：
文献类型：
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作者：
Daniel C. Bowers;Saijun Fan;Kevin A. Walter;R. Abounader;Jeffery A. Williams;E. Rosen;J. Laterra
我们最近已经表明，多功能生长因子，分散因子/肝细胞生长因子（SF/HGF），及其受体c-met通过自分泌刺激环增强人胶质母细胞瘤的恶性度（R. Abounader等人，J. Natl.癌症研究所，91：1548-1556，1999）。本报告探讨了SF/HGF：c-met信号对人脑胶质瘤细胞对DNA损伤剂反应的影响。用重组SF/HGF预处理U373人胶质母细胞瘤细胞部分消除了它们对γ射线、顺铂、喜树碱、阿霉素和紫杉醇的体外细胞毒性反应。SF/HGF的这种细胞保护作用至少部分通过抑制细胞凋亡而发生，如末端脱氧核苷酸转移酶介导的dUTP缺口末端标记指数降低和DNA梯状化减少所证明的。抗c-met U1/核酶基因转移抑制SF/HGF保护免受DNA损伤剂引起的单链DNA断裂、DNA片段化和胶质母细胞瘤细胞死亡的能力，表明需要c-met受体功能。SF/HGF处理U373细胞后，细胞存活促进激酶Akt（蛋白激酶B）磷酸化，Akt磷酸化和SF/HGF诱导的细胞存活均被磷脂酰肌醇3-激酶抑制剂抑制，但不被丝裂原活化蛋白激酶激酶或蛋白激酶C抑制剂抑制。SF/HGF在体外的细胞保护作用也被显性阴性Akt的瞬时表达抑制。颅内9 L胶质瘤的转基因SF/HGF表达降低了肿瘤细胞对γ射线的敏感性，证实了SF/HGF在体内的细胞保护作用。这些研究结果表明，c-met受体激活SF/HGF保护某些胶质母细胞瘤细胞的DNA损伤剂通过激活磷酸肌醇3-激酶依赖性和Akt依赖性抗凋亡途径。
We have shown recently that the multifunctional growth factor, scatter factor/hepatocyte growth factor (SF/HGF), and its receptor c-met enhance the malignancy of human glioblastoma through an autocrine stimulatory loop (R. Abounader et al., J. Natl. Cancer Inst., 91: 1548-1556, 1999). This report examines the effects of SF/HGF:c-met signaling on human glioma cell responses to DNA-damaging agents. Pretreating U373 human glioblastoma cells with recombinant SF/HGF partially abrogated their cytotoxic responses to gamma irradiation, cisplatin, camptothecin, Adriamycin, and Taxol in vitro. This cytoprotective effect of SF/HGF occurred at least in part through an inhibition of apoptosis, as evidenced by diminished terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling index and reduced DNA laddering. Anti-c-met U1/ribozyme gene transfer inhibited the ability of SF/HGF to protect against single-strand DNA breakage, DNA fragmentation, and glioblastoma cell death caused by DNA-damaging agents, demonstrating a requirement for c-met receptor function. Phosphorylation of the cell survival-promoting kinase Akt (protein kinase B) resulted from SF/HGF treatment of U373 cells, and both Akt phosphorylation and cell survival induced by SF/HGF were inhibited by phosphatidylinositol 3-kinase inhibitors but not by inhibitors of mitogen-activated protein kinase kinase or protein kinase C. Cytoprotection by SF/HGF in vitro was also inhibited by transient expression of dominant-negative Akt. Transgenic SF/HGF expression by intracranial 9L gliosarcomas reduced tumor cell sensitivity to gamma irradiation, confirming the cytoprotective effect of SF/HGF in vivo. These findings demonstrate that c-met receptor activation by SF/HGF protects certain glioblastoma cells from DNA-damaging agents by activating phosphoinositol 3-kinase-dependent and Akt-dependent antiapoptotic pathways.