Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade
Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade
复制标题
DOI：
10.1158/1535-7163.mct-05-0068
复制
发表时间：
2005-10-01
影响因子：
5.7
通讯作者：
Lichtenstein, A
中科院分区：
文献类型：
--
作者：
Shi, YJ;Yan, HJ;Lichtenstein, A
哺乳动物雷帕霉素靶点 (mTOR) 抑制剂，例如雷帕霉素和 CCI-779，已显示出治疗多发性骨髓瘤的临床前潜力。通过抑制细胞周期蛋白的表达，这些药物诱导 G1 停滞。然而，通过抑制胰岛素受体底物 1 (IRS-1) 的 mTOR 依赖性丝氨酸磷酸化，它们可以增强胰岛素样生长因子 1 (IGF-1) 信号传导和下游磷脂酰肌醇 3-激酶 (PI3K)/AKT 激活。这可能是多发性骨髓瘤中的一个特殊问题，其中 IGF-1 诱导的 AKT 激活是重要的抗凋亡级联反应。因此，我们研究了用 mTOR 抑制剂处理的多发性骨髓瘤细胞中的 AKT 激活。雷帕霉素增强多发性骨髓瘤细胞中的基础 AKT 活性、AKT 磷酸化和 PI3K 活性，并延长外源性 IGF-I 诱导的 AKT 激活。用于异种移植模型的 CCI-779 也导致体内多发性骨髓瘤细胞 AKT 激活。阻断 IGF-I 受体功能可阻止雷帕霉素激活 AKT。此外，雷帕霉素可防止 IRS-1 的丝氨酸磷酸化，增强 IRS-1 与 IGF-I 受体的结合，并防止 IRS-1 降解。尽管蛋白酶体抑制剂同样能阻止 IRS-1 降解，但不会激活 AKT。因此，mTOR 抑制剂可激活多发性骨髓瘤细胞中的 PI3-K/AKT；激活取决于基础 IGF-R 信号传导；抑制 IRS-1 丝氨酸磷酸化继发的 IRS-1/IGF-I 受体相互作用增强可能在级联激活中发挥作用。在联合治疗实验中，雷帕霉素抑制 PS-341 诱导的骨髓瘤细胞凋亡。这些结果为未来在骨髓瘤患者中使用 mTOR 抑制剂（如果它们与凋亡诱导剂联合使用）提供了警告。
Mammalian target of rapamycin (mTOR) inhibitors, such as rapamycin and CCI-779, have shown preclinical potential as therapy for multiple myeloma. By inhibiting expression of cell cycle proteins, these agents induce G, arrest. However, by also inhibiting an mTOR-dependent serine phosphorylation of insulin receptor substrate-1 (IRS-1), they may enhance insulin-like growth factor-1 (IGF-1) signaling and downstream phosphatidylinositol 3-kinase (PI3K)/AKT activation. This may be a particular problem in multiple myeloma where IGF-1-induced activation of AKT is an important antiapoptotic cascade. We, therefore, studied AKT activation in multiple myeloma cells treated with mTOR inhibitors. Rapamycin enhanced basal AKT activity, AKT phosphorylation, and PI3K activity in multiple myeloma cells and prolonged activation of AKT induced by exogenous IGF-I. CCI-779, used in a xenograft model, also resulted in multiple myeloma cell AKT activation in vivo. Blockade of lGF-I receptor function prevented rapamycin's activation of AKT. Furthermore, rapamycin prevented serine phosphorylation of IRS-1, enhanced IRS-1 association with IGF-I receptors, and prevented IRS-1 degradation. Although similarly blocking IRS-1 degradation, proteasome inhibitors did not activate AKT. Thus, mTOR inhibitors activate PI3-K/AKT in multiple myeloma cells; activation depends on basal IGF-R signaling; and enhanced IRS-1/IGF-I receptor interactions secondary to inhibited IRS-1 serine phosphorylation may play a role in activation of the cascade. In cotreatment experiments, rapamycin inhibited myeloma cell apoptosis induced by PS-341. These results provide a caveat for future use of mTOR inhibitors in myeloma patients if they are to be combined with apoptosis-inducing agents.