Activation of pro-apoptotic p38-MAPK pathway in the prostate cancer cell line M12 expressing a truncated IGF-IR.
Activation of pro-apoptotic p38-MAPK pathway in the prostate cancer cell line M12 expressing a truncated IGF-IR.
复制标题
表达截短的 IGF-IR 的前列腺癌细胞系 M12 中促凋亡 p38-MAPK 通路的激活。
DOI：
10.1055/s-2004-814160
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发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Plymate,SR
中科院分区：
文献类型：
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作者：
Wu,J;Haugk,K;Plymate,SR
I型胰岛素样生长因子受体（IGF-IR）在许多细胞类型的存活和增殖信号中起关键作用。IGF-IR通过其配体激活通过促分裂原活化蛋白激酶（MAPK）级联促进细胞增殖，并通过磷酸肌醇3-激酶（PI 3 K）级联促进细胞存活。IGF-IR作为许多肿瘤细胞的强大生长因子出现。一个截短的IGF-IR 486/STOP，被描述为一个显性负性IGF-IR突变体，被证明在体内诱导细胞凋亡和抑制肿瘤生长，而内源性IGF-IR被激活。为了研究486/STOP的作用机制，我们已经将486/STOP引入前列腺肿瘤模型细胞系M12及其衍生物M12 lisn中，该细胞系表达高水平的野生型IGF-IR。我们已经发现486/STOP诱导培养的M12和M12 lisn细胞的凋亡，并且486/STOP通过激活促凋亡p38而起作用。MAPK而不干扰野生型IGF-IR活化。此外，我们的研究结果表明486/STOP通过激活内源性IGF-IR而增强p38-MAPK的激活，提示486/STOP对IGF-IR的激活可以选择性地增强先前报道的IGF-IR促凋亡信号通路。
The type I insulin-like growth factor receptor (IGF-IR) plays a critical role in signaling survival and proliferation in many cell types. Activation of IGF-IR by its ligands promotes cell proliferation via mitogen-activated protein kinase (MAPK) cascade and cell survival via phosphoinositide 3-kinase (PI3K) cascade. The IGF-IR emerges as a powerful growth factor for many tumor cells. A truncated IGF-IR 486/STOP, described as a dominant negative IGF-IR mutant, was shown to induce apoptosis and inhibit tumor growth in vivo while endogenous IGF-IR was activated. To investigate the mechanism (s) of the action of 486/STOP, we have introduced 486/STOP into the prostate tumor model cell line M12 and its derivative M12lisn that expresses high levels of wild type IGF-IR. We have found that 486/STOP induces apoptosis in M12 and M12lisn cells in culture and that 486/STOP acts through activation of the pro-apoptotic p38-MAPK without interfering with wild type IGF-IR activation. In addition, our results have indicated that 486/STOP induced activation of p38-MAPK increases through activation of endogenous IGF-IR. These data suggest that activation of the IGF-IR by 486/STOP can selectively enhance the previously reported IGF-IR pro-apoptotic signaling pathways.