Oncotarget

Research Papers:

Computational modeling of methionine cycle-based metabolism and DNA methylation and the implications for anti-cancer drug response prediction

Mengying Zhang, Christian Saad, Lien Le, Kathrin Halfter, Bernhard Bauer, Ulrich R. Mansmann and Jian Li _

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Oncotarget. 2018; 9:22546-22558. https://doi.org/10.18632/oncotarget.24547

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Abstract

Mengying Zhang1, Christian Saad4, Lien Le1, Kathrin Halfter1, Bernhard Bauer4, Ulrich R. Mansmann1,2 and Jian Li1,2,3

1Institute for Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians University of München, Munich, Germany

2German Cancer Consortium (DKTK), Heidelberg, Germany

3German Cancer Research Center (DKFZ), Heidelberg, Germany

4Department of Computational Science, University of Augsburg, Augsburg, Germany

Correspondence to:

Jian Li, email: lijian@ibe.med.uni-muenchen.de

Keywords: metabolism; methylation; chemotherapy; molecular modelling; treatment prediction

Received: July 06, 2017    Accepted: July 29, 2017    Epub: February 21, 2018    Published: April 27, 2018

ABSTRACT

The relationship between metabolism and methylation is considered to be an important aspect of cancer development and drug efficacy. However, it remains poorly defined how to apply this aspect to improve preclinical disease characterization and clinical treatment outcome. Using available molecular information from Kyoto Encyclopedia of Genes and Genomes (KEGG) and literature, we constructed a large-scale knowledge-based metabolic in silico model. For the purpose of model validation, we applied data from the Cancer Cell Line Encyclopedia (CCLE) to investigate computationally the impact of metabolism on chemotherapy efficacy. In our model, different metabolic components such as MAT2A, ATP6V0E1, NNMT involved in methionine cycle correlate with biologically measured chemotherapy outcome (IC50) that are in agreement with findings of independent studies. These proteins are potentially also involved in cellular methylation processes. In addition, several components such as 3,4-dihydoxymandelate, PAPSS2, UPP1 from metabolic pathways involved in the production of purine and pyrimidine correlate with IC50. This study clearly demonstrates that complex computational approaches can reflect findings of biological experiments. This demonstrates their high potential to grasp complex issues within systems medicine such as response prediction, biomarker identification using available data resources.


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