Low Energy Status under Methionine Restriction Is Essentially Independent of Proliferation or Cell Contact Inhibition.

Corinna Koderer,Christian Linz,Anna Chiara Wünsch,Axel Seher,Werner Schmitz,Stefan Hartmann,Julian Manuel Volland,Alexander Christian Kübler,Mohamed El-Mesery,Julia Balint

doi:10.3390/cells11030551

Abstract

Nonlimited proliferation is one of the most striking features of neoplastic cells. The basis of cell division is the sufficient presence of mass (amino acids) and energy (ATP and NADH). A sophisticated intracellular network permanently measures the mass and energy levels. Thus, in vivo restrictions in the form of amino acid, protein, or caloric restrictions strongly affect absolute lifespan and age-associated diseases such as cancer. The induction of permanent low energy metabolism (LEM) is essential in this process. The murine cell line L929 responds to methionine restriction (MetR) for a short time period with LEM at the metabolic level defined by a characteristic fingerprint consisting of the molecules acetoacetate, creatine, spermidine, GSSG, UDP-glucose, pantothenate, and ATP. Here, we used mass spectrometry (LC/MS) to investigate the influence of proliferation and contact inhibition on the energy status of cells. Interestingly, the energy status was essentially independent of proliferation or contact inhibition. LC/MS analyses showed that in full medium, the cells maintain active and energetic metabolism for optional proliferation. In contrast, MetR induced LEM independently of proliferation or contact inhibition. These results are important for cell behaviour under MetR and for the optional application of restrictions in cancer therapy.

Highlights

A late event in the development of cancer is unlimited proliferation and the resulting space-occupying lesion
We investigated the extent to which contact inhibition affects the metabolism of L929 cells and whether inhibition of proliferation induces a metabolic profile equivalent to that of low energy metabolism (LEM)
The murine cell line L929 has fulfilled these conditions. This cell line corresponds to fibroblasts, which are characterised by a general profile in contrast to neurons or hepatocytes, which are highly specialised

Summary

Introduction

A late event in the development of cancer is unlimited proliferation and the resulting space-occupying lesion. The pathological causes of carcinogenesis are diverse [1] and proliferation is an important biological process regulated and influenced by numerous factors [2,3,4], this process can be reduced to two simple regulating components: the availability of energy and mass. Both factors are essential, and proliferation can be fundamentally regulated via both elements. In the case of mass, amino acids are paramount. In the case of energy, carbohydrates and lipids are more important initially and essentially result in the energy currencies ATP and NAD(P)H

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