The space of enzyme regulation in HeLa cells can be inferred from its intracellular metabolome

Abstract

During the transition from a healthy state to a cancerous one, cells alter their metabolism to increase proliferation. The underlying metabolic alterations may be caused by a variety of different regulatory events on the transcriptional or post-transcriptional level whose identification contributes to the rational design of therapeutic targets. We present a mechanistic strategy capable of inferring enzymatic regulation from intracellular metabolome measurements that is independent of the actual mechanism of regulation. Here, enzyme activities are expressed by the space of all feasible kinetic constants (k-cone) such that the alteration between two phenotypes is given by their corresponding kinetic spaces. Deriving an expression for the transformation of the healthy to the cancer k-cone we identified putative regulated enzymes between the HeLa and HaCaT cell lines. We show that only a few enzymatic activities change between those two cell lines and that this regulation does not depend on gene transcription but is instead post-transcriptional. Here, we identify phosphofructokinase as the major driver of proliferation in HeLa cells and suggest an optional regulatory program, associated with oxidative stress, that affects the activity of the pentose phosphate pathway.

Inference of cancer mechanisms through computational systems analysis

“…In a different approach, Diener and colleagues used k -cone analysis to quantify enzyme regulation in HeLa cells from the intracellular metabolome 24 . This strategy assumes that the metabolic network is at a steady state and uses stoichiometric models to characterize the relationship between fluxes, which are represented by mass action laws.…”

Host-Microbiome Interaction and Cancer: Potential Application in Precision Medicine

“…With the aim of disentangling this complex metabolic communication and surveying the metabolic pathways that actively participate in the community, metabolomics–embracing the massive quantitative measurement of intracellular or extracellular metabolites in biological samples such as human stool (Weir et al, 2013)–has been established as the more suitable HT technology to characterize the phenotype and dynamic response of living systems (Nicholson and Lindon, 2008; Marcobal et al, 2013; Diener et al, 2016). …”

“…Currently, the HMDB has more than 40,000 metabolite entries (Wishart et al, 2012). The enrichment of these valuable tools can provide a better understanding of the characteristics of health and disease states when combined with other clinical and modeling approaches to fill the gap between the genotype and phenotype relationship (Diener et al, 2016). …”

Biodegradable Nanoparticles Made of Amino-Acid-Based Ester Polymers: Preparation, Characterization, and In Vitro Biocompatibility Study

“…Generally, it has been shown recently that HeLa cells have some peculiarities in their metabolism [49,50]. A lower proteolytic activity can lead to a slower degradation of the 8L6 NPs inside the cells and, consequently, might cause increased cytotoxicity.…”