Membrane rafts segregate pro- from anti-apoptotic insulin-like growth factor-I receptor signaling in colon carcinoma cells stimulated by members of the tumor necrosis factor superfamily
Membrane rafts segregate pro- from anti-apoptotic insulin-like growth factor-I receptor signaling in colon carcinoma cells stimulated by members of the tumor necrosis factor superfamily
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DOI：
10.1016/s0002-9440(10)62049-4
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发表时间：
2005-09-01
影响因子：
6
通讯作者：
Pommier, G
中科院分区：
文献类型：
--
作者：
Remacle-Bonnet, M;Garrouste, F;Pommier, G
在肿瘤微环境中，胰岛素样生长因子（IGF）的自分泌/旁分泌环有助于癌细胞存活。然而，我们在这里报告说，IGF-I可以发送相互矛盾的信号，干扰肿瘤坏死因子（TNF）超家族的不同配体诱导的细胞死亡。IGF-I保护人结肠癌细胞免受TNF-α诱导的凋亡，但它增强了抗Fas抗体和TNF相关的凋亡诱导配体刺激的凋亡反应。在几种但不是所有测试的结肠癌细胞系中观察到的IGF-I的这种促凋亡作用是通过磷脂酰肌醇3 '-激酶（PI 3 K）/Akt途径介导的。此外，IGF-I受体（IGF-IR）位于膜脂筏内和膜脂筏外，并在IGF-I的作用下发生酪氨酸自磷酸化。然而，通过急性胆固醇耗竭破坏筏将IGF-IR转移到非筏结构域，消除IGF-I介导的促凋亡作用，并抑制IGF-I依赖性IRS-1和Akt募集到脂筏内并磷酸化/活化。用胆固醇补充细胞膜可以逆转这些效应。表达IGF-I抗凋亡作用的细胞外调节激酶-1/2和p38丝裂原活化蛋白激酶的激活独立于脂筏发生。因此，我们认为IGF-IR在脂筏内外的分离可以动态调节IGF-I对TNF超家族成员诱导的细胞凋亡的促凋亡和抗凋亡作用。
in the tumor microenvironment, autocrine/paracrine loops of insulin-like growth factors (IGFs) contribute to cancer cell survival. However, we report here that IGF-I can send contradictory signals that interfere with cell death induced by different ligands of the tumor necrosis factor (TNF) superfamily. IGF-I protected human colon carcinoma cells from TNF-alpha-induced apoptosis, but it enhanced the apoptotic response to anti-Fas antibody and TNF-related apoptosis inducing ligand stimulation. This proapoptotic effect of IGF-I, observed in several but not all tested colon cancer cell lines, was mediated via the phosphatidylinositol 3'-kinase (PI3K)/Akt pathway. Furthermore, IGF-I receptors (IGF-IR) were located in and out of membrane lipid rafts and were tyrosine autophosphorylated in response to IGF-I. However, disruption of rafts by acute cholesterol depletion shifted IGF-IR to non-raft domains, abolished the IGF-I-mediated proapoptotic effect, and inhibited the IGF-I-dependent IRS-1 and Akt recruitment into and phosphorylation/activation within lipid rafts. Replenishing cell membranes with cholesterol reversed these effects. Activation of extracellular-regulated kinase-1/2 and p38 mitogen-activated protein kinase, which convey the IGF-I anti-apoptotic effect, occurred independently of lipid rafts. Thus, we propose that segregation of IGF-IR in and out of lipid rafts may dynamically regulate the pro- and anti-apoptotic effects of IGF-I on apoptosis induced by TNF superfamily members.