Activated Oncogenic Pathway Modifies Iron Network in Breast Epithelial Cells: A Dynamic Modeling Perspective.
Activated Oncogenic Pathway Modifies Iron Network in Breast Epithelial Cells: A Dynamic Modeling Perspective.
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DOI：
10.1371/journal.pcbi.1005352
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发表时间：
2017-02
影响因子：
4.3
通讯作者：
Laubenbacher R
中科院分区：
文献类型：
--
作者：
Chifman J;Arat S;Deng Z;Lemler E;Pino JC;Harris LA;Kochen MA;Lopez CF;Akman SA;Torti FM;Torti SV;Laubenbacher R
癌症中铁代谢的失调是有据可查的，并且已经表明过量的铁与增加的癌症发病率和进展之间存在相互依赖性。为了更好地理解铁代谢和乳腺癌之间的联系，构建了一个扩展的铁稳态途径的预测数学模型，其中包括参与铁利用，氧化应激反应和致癌途径的物种。该模型得出三个预测。第一个是铁调节蛋白2（IRP2）的过表达概括了癌细胞中游离铁和铁相关蛋白的改变的许多方面，而不影响模型中包括的氧化应激反应或致癌途径。这一预测得到了实验的验证。第二个预测是铁相关蛋白质受到线粒体铁蛋白过表达的显著影响。这一预测得到了验证的结果，在相关文献中没有用于模型构建。第三个预测是致癌Ras通路有助于改变癌细胞中的铁稳态。结合Ras过表达和过氧化氢酶敲除的模拟实验，结合文献，验证了这一预测。该模型成功地捕获了乳腺癌细胞中铁代谢的关键方面，并提供了一个框架，可以在此基础上建立更详细的模型。铁是细胞代谢和生长所必需的，但由于其能够引起高氧化应激并因此导致DNA损伤，因此可能是有毒的。为了防止损伤，所有需要铁的生物体都开发了严格控制铁水平的机制。铁代谢的失调是有害的，并可能导致包括癌症在内的多种疾病。本文提出了一个预测的数学模型，铁的调节与铁的利用，氧化应激，和特定的正常乳腺上皮细胞的致癌反应。该模型使用离散建模框架来生成新的生物学假设，用于研究正常乳腺细胞如何变成恶性细胞，通过过表达和敲除模拟捕获铁稳态的乳腺癌表型。新发现的生物学是（1）IRP2过表达改变乳腺细胞中的铁稳态途径，而不影响氧化应激反应或致癌途径，（2）激活的致癌途径破坏乳腺癌细胞中的铁调节。
Dysregulation of iron metabolism in cancer is well documented and it has been suggested that there is interdependence between excess iron and increased cancer incidence and progression. In an effort to better understand the linkages between iron metabolism and breast cancer, a predictive mathematical model of an expanded iron homeostasis pathway was constructed that includes species involved in iron utilization, oxidative stress response and oncogenic pathways. The model leads to three predictions. The first is that overexpression of iron regulatory protein 2 (IRP2) recapitulates many aspects of the alterations in free iron and iron-related proteins in cancer cells without affecting the oxidative stress response or the oncogenic pathways included in the model. This prediction was validated by experimentation. The second prediction is that iron-related proteins are dramatically affected by mitochondrial ferritin overexpression. This prediction was validated by results in the pertinent literature not used for model construction. The third prediction is that oncogenic Ras pathways contribute to altered iron homeostasis in cancer cells. This prediction was validated by a combination of simulation experiments of Ras overexpression and catalase knockout in conjunction with the literature. The model successfully captures key aspects of iron metabolism in breast cancer cells and provides a framework upon which more detailed models can be built. Iron is required for cellular metabolism and growth, but can be toxic due to its ability to cause high oxidative stress and consequently DNA damage. To prevent damage, all organisms that require iron have developed mechanisms to tightly control iron levels. Dysregulation of iron metabolism is detrimental and can contribute to a wide range of diseases, including cancer. This paper presents a predictive mathematical model of iron regulation linked to iron utilization, oxidative stress, and the oncogenic response specific to normal breast epithelial cells. The model uses a discrete modeling framework to generate novel biological hypotheses for an investigation of how normal breast cells become malignant cells, capturing a breast cancer phenotype of iron homeostasis through overexpression and knockout simulations. The new biology discovered is (1) IRP2 overexpression alters the iron homeostasis pathway in breast cells, without affecting the oxidative stress response or oncogenic pathways, (2) an activated oncogenic pathway disrupts iron regulation in breast cancer cells.
影响因子：
4
作者：
Xie Z;Harrison SH;Torti SV;Torti FM;Han J
通讯作者：
Han J