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Deciphering Signaling Pathway Networks to Understand the Molecular Mechanisms of Metformin Action

文献类型：期刊论文

作者Sun, Jingchun6,7; Zhao, Min7; Jia, Peilin7; Wang, Lily8; Wu, Yonghui6; Iverson, Carissa9,10; Zhou, Yubo11; Bowton, Erica12; Roden, Dan M.1,5; Denny, Joshua C.7
刊名PLOS COMPUTATIONAL BIOLOGY
出版日期2015-06
卷号11期号:6
ISSN号1553-734X
DOI10.1371/journal.pcbi.1004202
文献子类Article
英文摘要A drug exerts its effects typically through a signal transduction cascade, which is non-linear and involves intertwined networks of multiple signaling pathways. Construction of such a signaling pathway network (SPNetwork) can enable identification of novel drug targets and deep understanding of drug action. However, it is challenging to synopsize critical components of these interwoven pathways into one network. To tackle this issue, we developed a novel computational framework, the Drug-specific Signaling Pathway Network (DSPathNet). The DSPathNet amalgamates the prior drug knowledge and drug-induced gene expression via random walk algorithms. Using the drug metformin, we illustrated this framework and obtained one metformin-specific SPNetwork containing 477 nodes and 1,366 edges. To evaluate this network, we performed the gene set enrichment analysis using the disease genes of type 2 diabetes (T2D) and cancer, one T2D genome-wide association study (GWAS) dataset, three cancer GWAS datasets, and one GWAS dataset of cancer patients with T2D on metformin. The results showed that the metformin network was significantly enriched with disease genes for both T2D and cancer, and that the network also included genes that may be associated with metformin-associated cancer survival. Furthermore, from the metformin SPNetwork and common genes to T2D and cancer, we generated a subnetwork to highlight the molecule crosstalk between T2D and cancer. The follow-up network analyses and literature mining revealed that seven genes (CDKN1A, ESR1, MAX, MYC, PPARGC1A, SP1, and STK11) and one novel MYC-centered pathway with CDKN1A, SP1, and STK11 might play important roles in metformin's antidiabetic and anticancer effects. Some results are supported by previous studies. In summary, our study 1) develops a novel framework to construct drug-specific signal transduction networks; 2) provides insights into the molecular mode of metformin; 3) serves a model for exploring signaling pathways to facilitate understanding of drug action, disease pathogenesis, and identification of drug targets.
WOS关键词GENOME-WIDE ASSOCIATION ; GENE-EXPRESSION SIGNATURES ; C-MYC ; TRANSCRIPTION FACTORS ; DIABETES-MELLITUS ; DRUG-DISCOVERY ; CANCER-CELLS ; IN-VIVO ; INSULIN-RESISTANCE ; PANCREATIC-CANCER
资助项目National Institutes of Health[R01LM011177] ; National Institutes of Health[R01LM 010685] ; National Institutes of Health[K07CA172294] ; National Institutes of Health[P50CA90949] ; National Institutes of Health[P50CA095103] ; National Institutes of Health[P50CA098131] ; National Institutes of Health[P30CA068485] ; National Institutes of Health[RC2 GM092618] ; National Institutes of Health[ULTR000445] ; Cancer Prevention & Research Institute of Texas Rising Star Award[CPRIT R1307] ; NARSAD Young Investigator Award[00000000] ; American Cancer Society Institutional Research Grant pilot project[IRG-58-009-55] ; Ingram Professorship Funds[00000000]
WOS研究方向Biochemistry & Molecular Biology ; Mathematical & Computational Biology
语种英语
WOS记录号WOS:000357340100006
出版者PUBLIC LIBRARY SCIENCE
源URL[http://119.78.100.183/handle/2S10ELR8/276503]  
专题国家新药筛选中心
通讯作者Sun, Jingchun
作者单位1.Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA;
2.Vanderbilt Univ, Sch Med, Div Epidemiol, Nashville, TN 37212 USA;
3.Vanderbilt Univ, Sch Med, Ctr Quantitat Sci, Nashville, TN 37212 USA;
4.Vanderbilt Univ, Sch Med, Dept Canc Biol, Nashville, TN 37212 USA
5.Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN 37212 USA;
6.Univ Texas Hlth Sci Ctr Houston, Sch Biomed Informat, Houston, TX 77030 USA;
7.Vanderbilt Univ, Sch Med, Dept Biomed Informat, Nashville, TN 37212 USA;
8.Vanderbilt Univ, Sch Med, Dept Biostat, Nashville, TN 37212 USA;
9.Vanderbilt Univ, Sch Med, Dept Thorac Surg, Nashville, TN 37212 USA;
10.Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN 37235 USA;
推荐引用方式
GB/T 7714		 Sun, Jingchun,Zhao, Min,Jia, Peilin,et al. Deciphering Signaling Pathway Networks to Understand the Molecular Mechanisms of Metformin Action[J]. PLOS COMPUTATIONAL BIOLOGY,2015,11(6).
APA Sun, Jingchun.,Zhao, Min.,Jia, Peilin.,Wang, Lily.,Wu, Yonghui.,...&Zhao, Zhongming.(2015).Deciphering Signaling Pathway Networks to Understand the Molecular Mechanisms of Metformin Action.PLOS COMPUTATIONAL BIOLOGY,11(6).
MLA Sun, Jingchun,et al."Deciphering Signaling Pathway Networks to Understand the Molecular Mechanisms of Metformin Action".PLOS COMPUTATIONAL BIOLOGY 11.6(2015).

入库方式： OAI收割

来源：上海药物研究所

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