使用系统生物学方法对用于耐药性研究的p38丝裂原活化蛋白激酶亚型进行表征。
Characterization of p38 MAPK isoforms for drug resistance study using systems biology approach.
作者信息
Peng Huiming, Peng Tao, Wen Jianguo, Engler David A, Matsunami Risë K, Su Jing, Zhang Le, Chang Chung-Che Jeff, Zhou Xiaobo
机构信息
Center for Bioinformatics & Systems Biology and Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA, Department of Radiology, The Methodist Hospital Research Institute, Houston, TX 77030, USA, Department of Pathology, The Methodist Hospital Research Institute, Houston, TX 77030, USA, Proteomics Programmatic Core Laboratory, The Methodist Hospital Research Institute, Houston, TX 77030, USA, College of Computer and Information Science, Southwest University, Chongqing 400715, China, Department of Pathology, Florida Hospital, Orlando, FL 32803, USA.
Center for Bioinformatics & Systems Biology and Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA, Department of Radiology, The Methodist Hospital Research Institute, Houston, TX 77030, USA, Department of Pathology, The Methodist Hospital Research Institute, Houston, TX 77030, USA, Proteomics Programmatic Core Laboratory, The Methodist Hospital Research Institute, Houston, TX 77030, USA, College of Computer and Information Science, Southwest University, Chongqing 400715, China, Department of Pathology, Florida Hospital, Orlando, FL 32803, USACenter for Bioinformatics & Systems Biology and Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA, Department of Radiology, The Methodist Hospital Research Institute, Houston, TX 77030, USA, Department of Pathology, The Methodist Hospital Research Institute, Houston, TX 77030, USA, Proteomics Programmatic Core Laboratory, The Methodist Hospital Research Institute, Houston, TX 77030, USA, College of Computer and Information Science, Southwest University, Chongqing 400715, China, Department of Pathology, Florida Hospital, Orlando, FL 32803, USA.
出版信息
Bioinformatics. 2014 Jul 1;30(13):1899-907. doi: 10.1093/bioinformatics/btu133. Epub 2014 Mar 10.
MOTIVATION
p38 mitogen-activated protein kinase activation plays an important role in resistance to chemotherapeutic cytotoxic drugs in treating multiple myeloma (MM). However, how the p38 mitogen-activated protein kinase signaling pathway is involved in drug resistance, in particular the roles that the various p38 isoforms play, remains largely unknown.
METHOD
To explore the underlying mechanisms, we developed a novel systems biology approach by integrating liquid chromatography-mass spectrometry and reverse phase protein array data from human MM cell lines with computational pathway models in which the unknown parameters were inferred using a proposed novel algorithm called modularized factor graph.
RESULTS
New mechanisms predicted by our models suggest that combined activation of various p38 isoforms may result in drug resistance in MM via regulating the related pathways including extracellular signal-regulated kinase (ERK) pathway and NFкB pathway. ERK pathway regulating cell growth is synergistically regulated by p38δ isoform, whereas nuclear factor kappa B (NFкB) pathway regulating cell apoptosis is synergistically regulated by p38α isoform. This finding that p38δ isoform promotes the phosphorylation of ERK1/2 in MM cells treated with bortezomib was validated by western blotting. Based on the predicted mechanisms, we further screened drug combinations in silico and found that a promising drug combination targeting ERK1/2 and NFκB might reduce the effects of drug resistance in MM cells. This study provides a framework of a systems biology approach to studying drug resistance and drug combination selection.
AVAILABILITY AND IMPLEMENTATION
RPPA experimental Data and Matlab source codes of modularized factor graph for parameter estimation are freely available online at http://ctsb.is.wfubmc.edu/publications/modularized-factor-graph.php.
动机
p38丝裂原活化蛋白激酶的激活在多发性骨髓瘤（MM）化疗细胞毒性药物耐药中起重要作用。然而，p38丝裂原活化蛋白激酶信号通路如何参与耐药，尤其是各种p38亚型所起的作用，仍 largely 未知。
方法
为探究潜在机制，我们开发了一种新的系统生物学方法，将来自人类MM细胞系的液相色谱 - 质谱和反相蛋白质阵列数据与计算通路模型相结合，其中未知参数使用一种名为模块化因子图的新算法进行推断。
结果
我们模型预测的新机制表明，各种p38亚型的联合激活可能通过调节包括细胞外信号调节激酶（ERK）通路和NFкB通路在内的相关通路导致MM耐药。调节细胞生长的ERK通路由p38δ亚型协同调节，而调节细胞凋亡的核因子κB（NFкB）通路由p38α亚型协同调节。硼替佐米处理的MM细胞中p38δ亚型促进ERK1/2磷酸化这一发现通过蛋白质印迹得到验证。基于预测机制，我们进一步在计算机上筛选药物组合，发现一种有前景的靶向ERK1/2和NFκB的药物组合可能降低MM细胞的耐药作用。本研究提供了一种用于研究耐药和药物组合选择的系统生物学方法框架。
可用性和实现方式
RPPA实验数据和用于参数估计的模块化因子图的Matlab源代码可在http://ctsb.is.wfubmc.edu/publications/modularized-factor-graph.php免费在线获取。
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