Aurintricarboxylic acid induces a distinct activation of the IGF-I receptor signaling within MDA-231 cells
Aurintricarboxylic acid induces a distinct activation of the IGF-I receptor signaling within MDA-231 cells
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DOI：
10.1210/en.143.3.837
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发表时间：
2002-03-01
期刊：
影响因子：
4.8
通讯作者：
Geier, A
中科院分区：
文献类型：
--
作者：
Haimsohn, M;Beery, R;Geier, A
金三羧酸 (ATA) 是一种聚合羧化三苯甲烷衍生物，可防止多种细胞系统的细胞凋亡。最近，我们发现 ATA 的生存促进作用是通过激活 IGF-I 受体 (IGF-IR) 信号通路来转导的。在暴露于蛋白质合成抑制剂放线菌酮或蓖麻毒素或抗癌药物阿霉素的乳腺癌 MDA-231 细胞中，我们发现 ATA（而非 IGF-1）是一种强大的抗凋亡剂。本研究的目的是比较 ATA 和 IGF-1 激活 IGF-IR 信号级联的能力，并将这种能力与其生存效力相关联。 MDA-231 细胞暴露于 ATA 或 IGF-I 长达 7 小时，并评估 IGF-IR 信号级联激活的动态。我们的结果表明：1) 与 IGF-I 相比，暴露于 ATA 后酪氨酸磷酸化的 IGF-IR 蛋白的量更大。 2) 暴露于 ATA 后，诱导了两个磷酸化 IGF-IR,β 亚基（95-kDa 和 75-kDa），而 IGF-1 仅诱导 95-kDa 形式。通过针对 IGF-IR α 亚基和针对 IGF-IR β 亚基羧基末端的抗体对两种受体形式进行免疫沉淀，表明 75-kDa 形式可能是在 α-β 二硫键上方的氨基末端截断的 β 链。 3) 与IGF-I激活受体的快速去磷酸化相比，ATA激活的IGF-IR形式经历缓慢的去磷酸化。 4) 与 IGF-I 相比，胰岛素受体底物 1/2 相关的 PI3K、Shc 蛋白以及激酶 AM 和 Erk1/2（IGF-IR 抗凋亡信号传导的下游介质）被 ATA 激活的程度更高，持续时间更长。综上所述，ATA对IGF-IR信号通路的持续激活可能解释了其更强的抗凋亡作用。我们认为，这种增强的活性以及 IGF-IR 对某些蛋白酶和磷酸酶的不同敏感性可能表明 ATA 激活的 IGF-IR 具有不同的构象。
Aurintricarboxylic acid (ATA), a polymeric carboxylated triphenylmethane derivate, prevents apoptotic death in a variety of cell systems. Recently, we have shown that the survival promoting effect of ATA is transduced via activation of the IGF-I receptor (IGF-IR) signaling pathway. In breast cancer MDA-231 cells exposed either to the protein synthesis inhibitors cycloheximide or ricin or to the anticancer drug adriamycin, we have found that ATA, but not IGF-1, is a powerful antiapoptotic agent. The purpose of this study was to compare the ability of ATA and IGF-1 to activate the IGF-IR signaling cascade and to correlate this ability to their survival potency. MDA-231 cells were exposed to ATA or IGF-I, up to 7 h, and the dynamics of activation of the IGF-IR signaling cascade was evaluated. Our results show that: 1) The amount of tyrosine phosphorylated IGF-IR proteins was greater after exposure to ATA, compared with IGF-I. 2) Two phosphorylated IGF-IR,beta-subunits (a 95-kDa and a 75-kDa) were induced after exposure to ATA, whereas IGF-1 induced only the 95-kDa form. Immunoprecipitation of both receptor forms by antibodies against the alpha-subunit and against the carboxy terminus of the beta-subunit of the IGF-IR suggests that the 75-kDa form could be the beta-chain truncated at the amino terminus above the alpha-beta disulphide bridges. 3) The ATA-activated IGF-IR forms underwent slow dephosphorylation, compared with a rapid dephosphorylation of the IGF-I activated receptor. 4) The insulin receptor substrate-1/2-associated PI3K, Shc proteins, and the kinases AM and Erk1/2, downstream mediators of the antiapoptotic signaling by IGF-IR, were activated to a higher extent and for a longer time period by ATA, compared with IGF-I. Taken together, the sustained activation of the IGF-IR signaling pathway by ATA may explain its stronger antiapoptotic effect. We suggest that this enhanced activity, and the different susceptibility of the IGF-IR to certain proteases and phosphatases, may indicate a distinct conformation of the ATA-activated IGF-IR.