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首页> 外文期刊>Journal of applied toxicology >Comparison of intracellular signalling by insulin and the hypermitogenic AspB10 analogue in MCF-7 breast adenocarcinoma cells.
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Comparison of intracellular signalling by insulin and the hypermitogenic AspB10 analogue in MCF-7 breast adenocarcinoma cells.

机译：在MCF-7乳腺腺癌细胞中通过胰岛素和高促有丝分裂的AspB10类似物进行细胞内信号传导的比较。

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We compared mitogenicity and intracellular signalling by human insulin and the AspB10 (X-10) human insulin analogue in MCF-7 human mammary adenocarcinoma cells. By flow analysis of phosphorylated histone H3 or cell cycle distributions, insulin and X-10 were mitogenic at physiologically relevant concentrations (2 nm to 74 pm range), with X-10 being approximately 3-fold more mitogenic than insulin. By western blotting with phospho-specific antibodies, insulin induced phosphorylation of IRS-1, Akt, p70S6K, S6 ribosomal protein, 4E-BP1, FoxO3a, FoxO1, p44/42 MAPK and the EGFR. Blocking with wortmannin, rapamycin and U0126 showed that these signalling events conformed to the canonical PI3K pathway. IRS-1 (Ser302) phosphorylation was abolished by wortmannin and rapamycin, suggesting a feedback from the PI3K pathway on insulin signalling. Compared with equimolar insulin, X-10 caused up to 2-fold higher phosphorylation of all proteins examined in this study. The phosphorylation sites that responded most strongly to insulin were not generally the same as those responding most strongly to X-10. In the PI3K pathway, the most X-10-sensitive protein localized to the translation-regulating arm (p70S6K), with FoxO3a and FoxO1 transcription factors showing a more comparable response to insulin and X-10. Using flow analysis, we confirmed the correlation between insulin-triggered translational activation in G0/G1 (S6 phosphorylation) and S-phase entry by MCF-7 cells. In summary, our findings implicate asymmetrical PI3K pathway activation and specifically stimulation of protein translation in the hypermitogenic effect of insulin analogues such as X-10. It remains to be shown whether these findings are relevant to other human mammary cancer cell types. Copyright (c) 2010 John Wiley & Sons, Ltd.
机译：我们在MCF-7人乳腺腺癌细胞中比较了人胰岛素和AspB10（X-10）人胰岛素类似物的促细胞分裂性和细胞内信号传导。通过对磷酸化组蛋白H3或细胞周期分布的流动分析，胰岛素和X-10在生理相关浓度（2 nm至74 pm范围）内有丝分裂，其中X-10的有丝分裂作用比胰岛素高约3倍。通过磷酸特异性抗体的蛋白质印迹，胰岛素诱导了IRS-1，Akt，p70S6K，S6核糖体蛋白，4E-BP1，FoxO3a，FoxO1，p44 / 42 MAPK和EGFR的磷酸化。用渥曼青霉素，雷帕霉素和U0126阻断显示这些信号转导事件符合规范的PI3K途径。渥曼青霉素和雷帕霉素消除了IRS-1（Ser302）的磷酸化作用，表明PI3K途径对胰岛素信号的反馈作用。与等摩尔胰岛素相比，在该研究中，X-10引起的所有蛋白质的磷酸化程度提高了2倍。对胰岛素反应最强的磷酸化位点通常与对X-10反应最强的磷酸化位点不同。在PI3K途径中，对X-10-最敏感的蛋白质位于翻译调节臂（p70S6K），而FoxO3a和FoxO1转录因子对胰岛素和X-10的反应更相似。使用流动分析，我们证实了G0 / G1中胰岛素触发的翻译激活（S6磷酸化）与MCF-7细胞进入S期之间的相关性。总而言之，我们的发现暗示胰岛素类似物（例如X-10）的超有丝分裂作用中不对称的PI3K途径活化，特别是刺激蛋白质翻译。这些发现是否与其他人类乳腺癌细胞类型相关尚待证实。版权所有（c）2010 John Wiley＆Sons，Ltd.

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