Effect of insulin-like growth factor II on protecting myoblast cells against cisplatin-induced apoptosis through p70 s6 kinase pathway
Effect of insulin-like growth factor II on protecting myoblast cells against cisplatin-induced apoptosis through p70 s6 kinase pathway
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DOI：
10.1038/sj.neo.7900242
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发表时间：
2002-09-01
期刊：
影响因子：
4.8
通讯作者：
Helman, LJ
中科院分区：
文献类型：
--
作者：
Wan, XL;Helman, LJ
胰岛素样生长因子（IGF-II）在多种人类肿瘤中过表达，具有促有丝分裂和抗凋亡活性。虽然IGF-II诱导增殖的机制已经得到了很好的研究，其生存信号的机制还没有得到很好的表征。在这份报告中，我们研究了胰岛素样生长因子-II对顺铂诱导的细胞凋亡的作用。我们发现IGF-11的过度表达与p70核糖体蛋白S6激酶（p70 S6 K）的增加有关。顺铂处理C2 C12小鼠成肌细胞导致与p70 S6 K活性抑制相关的细胞死亡。内源性或外源性IGF-11对顺铂诱导的C2 C12细胞凋亡具有保护作用。在这两种情况下，这种保护与p70 S6 K基础活性的增加以及对顺铂诱导的活性降低的抗性有关。通过雷帕霉素阻断p70 S6 K活化，废除了IGF-II介导的对顺铂诱导的细胞凋亡的保护。此外，用雷帕霉素处理IGF-II过表达的Rh 30和CTR横纹肌肉瘤细胞恢复了对顺铂诱导的凋亡的敏感性。这些数据共同表明，IGF-II相关的顺铂诱导的细胞凋亡的保护作用是通过激活p70 S6 K途径介导的。因此，在IGF-II过表达肿瘤的治疗中，抑制p70 S6通路可增强化疗诱导的细胞凋亡。
Insulin-like growth factor (IGF-II) is overexpressed in a variety of human tumors and has both mitogenic and antiapoptotic activity. Although the mechanisms of IGF-II-induced proliferation have been well studied, the mechanisms underlying its survival signaling have been less well characterized. In this report, we investigated the role of IGF-II on cisplatin-induced apoptosis. We found that IGF-11 overexpression was associated with an increase in p70 ribosomal protein S6 kinase (p70 S6K). Cisplatin treatment of C2C12 mouse myoblasts led to cell death associated with an inhibition of p70 S6K activity. Endogenous or exogenous IGF-11 addition to C2C12 cells caused protection to cisplatin-induced apoptosis. This protection was associated in both cases with an increase in p70 S6K basal activity as well as resistance to cisplatin -induced decreased activity. Blockade of p70 S6K activation by rapamycin abrogated the IGF-II-mediated protection of cells to cisplatin-induced apoptosis. Furthermore, treatment of IGF-II-overexpressing Rh30 and CTR rhabdomyosarcoma cells with rapamycin restored sensitivity to cisplatininduced apoptosis. These data together suggest that IGF-II-associatedprotection to cisplatin-induced apoptosis is mediated through an activation of the p70 S6K pathway. Thus, inhibition of the p70 S6 pathway may enhance chemotherapy-induced apoptosis in the treatment of IGF-II-overexpressing tumors.