Integration of fluxome and transcriptome data in Saccharomyces cerevisiae offers unique features of doxorubicin and imatinib

Abstract

Improving the efficacy of drugs and developing new drugs are required to compensate for drug resistance. Therefore, it is critical to unveil the mode of action, which can be studied through the cellular response at genome-scale, of the existing drugs. Here, system-level response of Saccharomyces cerevisiae, a eukaryotic model microorganism, to two chemotherapy drugs doxorubicin and imatinib used against cancer are analysed. While doxorubicin is mainly known to interact with DNA through intercalation and imatinib is known to inhibit the activity of the tyrosine kinase enzyme, the exact mechanisms of action for both drugs have not been determined. The response of S. cerevisiae cells to long-term stress by these drugs under controlled aerobic conditions was investigated and analyzed by the genome-wide transcriptome and genome-wide fluxes. The classification of adverse and similar responses of a certain gene at a transcriptional versus flux level indicated the possible regulatory mechanisms under these different stress conditions. Most of the biochemical reactions were found to be regulated at a post-transcriptional or metabolic level, whereas fewer were regulated at a transcriptional level for both stress cases. Furthermore, disparately induced and repressed pathways in the metabolic network under doxorubicin and imatinib stress were identified. The glycolytic and pentose phosphate pathways responded similarly, whereas the purine-histidine metabolic pathways responded differently. Then, a comparison of differential fluxes and differentially co-expressed genes under doxorubicin and imatinib stress provided the potential common and unique features of these drugs. Analyzing such regulatory differences helps in resolving drug mechanisms and suggesting new drug targets.