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Exploring the differences in metabolic behavior of astrocyte and glioblastoma: a flux balance analysis approach

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Systems and Synthetic Biology

Abstract

Brain cancers demonstrate a complex metabolic behavior so as to adapt the external hypoxic environment and internal stress generated by reactive oxygen species. To survive in these stringent conditions, glioblastoma cells develop an antagonistic metabolic phenotype as compared to their predecessors, the astrocytes, thereby quenching the resources expected for nourishing the neurons. The complexity and cumulative effect of the large scale metabolic functioning of glioblastoma is mostly unexplored. In this study, we reconstruct a metabolic network comprising of pathways that are known to be deregulated in glioblastoma cells as compared to the astrocytes. The network, consisted of 147 genes encoding for enzymes performing 247 reactions distributed across five distinct model compartments, was then studied using constrained-based modeling approach by recreating the scenarios for astrocytes and glioblastoma, and validated with available experimental evidences. From our analysis, we predict that glycine requirement of the astrocytes are mostly fulfilled by the internal glycine–serine metabolism, whereas glioblastoma cells demand an external uptake of glycine to utilize it for glutathione production. Also, cystine and glucose were identified to be the major contributors to glioblastoma growth. We also proposed an extensive set of single and double lethal reaction knockouts, which were further perturbed to ascertain their role as probable chemotherapeutic targets. These simulation results suggested that, apart from targeting the reactions of central carbon metabolism, knockout of reactions belonging to the glycine–serine metabolism effectively reduce glioblastoma growth. The combinatorial targeting of glycine transporter with any other reaction belonging to glycine–serine metabolism proved lethal to glioblastoma growth.

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Acknowledgments

We thank Council of Scientific and Industrial Research, XII Five Year Plan Project “GENESIS” (BSC0121) and Department of Biotechnology, Government of India (Project Code: BT/PR13689/BID/07/363/2010) for providing financial support to perform this work. Abhishek Subramanian acknowledges the research fellowship provided by DBT-BINC fellowship program.

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Authors and Affiliations

  1. Chemical Engineering and Process Development, CSIR-National Chemical Laboratory, Pune, Maharashtra, 411008, India

    Rupa Bhowmick, Abhishek Subramanian & Ram Rup Sarkar

  2. Academy of Scientific and Innovative Research (AcSIR), CSIR-NCL Campus, Pune, 411008, India

    Abhishek Subramanian & Ram Rup Sarkar

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  1. Rupa Bhowmick
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  2. Abhishek Subramanian
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Correspondence to Ram Rup Sarkar.

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Bhowmick, R., Subramanian, A. & Sarkar, R.R. Exploring the differences in metabolic behavior of astrocyte and glioblastoma: a flux balance analysis approach. Syst Synth Biol 9, 159–177 (2015). https://doi.org/10.1007/s11693-015-9183-9

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  • DOI: https://doi.org/10.1007/s11693-015-9183-9

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