@phdthesis{Koderer2022,
  author    = {Koderer, Corinna},
  title     = {In Vitro Analyse der Methionin-Restriktion im murinen Modellsystem L929 sowie im Platteneptihelkarzinom - HNSCC},
  doi       = {10.25972/OPUS-27189},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-271897},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2022},
  abstract  = {Die Krebstherapie und Behandlung von Tumoren stellt f{\"u}r die moderne Medizin auch in Zukunft eine enorme Herausforderung dar. Trotz intensiver Forschung konnten in den letzten Jahrzehnten zwar zunehmend Fortschritte erzielt werden, allerdings muss das Spektrum an neuen Therapieformen und M{\"o}glichkeiten kontinuierlich erweitert werden. In den letzten Jahren haben die Kalorienrestriktion sowie die Aminos{\"a}uren- und Proteinrestriktion zunehmend an Bedeutung gewonnen, da sie einen erheblichen positiven Einfluss auf die Entstehung von altersassoziierten Erkrankungen wie z.B. Krebs haben. Allen Formen gemeinsam ist die Induktion eines Low-Energy-Metabolismus, der die Zellen in einen antiproliferativen und selbst-regenerierenden Zustand versetzt. In dieser Arbeit sollte untersucht werden, ob die Methionin-Restriktion als eine Form der Aminos{\"a}urerestriktion sich grunds{\"a}tzlich als Therapieform im Plattenepithelkarzinom (HNSCC) eignet. Zus{\"a}tzlich sollte ein einfaches zellul{\"a}res Modellsystem etabliert werden, das auf metaboler Ebene die Charakterisierung und Analyse des Low-Energy-Metabolismus erm{\"o}glicht. Es konnte aufgezeigt werden, dass die Methionin-Restriktion eine effektive Methode ist, um die Proliferation ausgesuchter Zelllinien des HNSCC zu inhibieren. Des Weiteren konnte aufgezeigt werden, dass der Einsatz von Aminos{\"a}ure-Analoga eine weitere M{\"o}glichkeit darstellt, auf die Proliferation von Tumorzellen Einfluss zu nehmen. Die massenspektrometrische Analyse der murinen Zelllinie L929 mittels LC/MS lieferte {\"u}ber einen Zeitraum von 5 Tagen ein detailliertes Bild des Stoffwechsels von mehr als 150 Metaboliten unter Methionin-Restriktion. Durch die Definition eines charakteristischen Fingerabdrucks nach 48 h und eines nur wenige Metabolite umfassenden Fußabdrucks konnte ein murines Modellsystem etabliert werden, dass die Analyse von potentiellen Wirkstoffen, u.a. sogenannten caloric restriction mimetics, erm{\"o}glicht.},
  language  = {de}
}
@article{KodererSchmitzWuenschetal.2022,
  author    = {Koderer, Corinna and Schmitz, Werner and W{\"u}nsch, Anna Chiara and Balint, Julia and El-Mesery, Mohamed and Volland, Julian Manuel and Hartmann, Stefan and Linz, Christian and K{\"u}bler, Alexander Christian and Seher, Axel},
  title     = {Low energy status under methionine restriction is essentially independent of proliferation or cell contact inhibition},
  series = {Cells},
  volume    = {11},
  journal   = {Cells},
  number    = {3},
  issn      = {2073-4409},
  doi       = {10.3390/cells11030551},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-262329},
  year      = {2022},
  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.},
  language  = {en}
}
@article{SchmitzKodererElMeseryetal.2021,
  author    = {Schmitz, Werner and Koderer, Corinna and El-Mesery, Mohamed and Gobik, Sebastian and Sampers, Rene and Straub, Anton and K{\"u}bler, Alexander Christian and Seher, Axel},
  title     = {Metabolic fingerprinting of murine L929 fibroblasts as a cell-based tumour suppressor model system for methionine restriction},
  series = {International Journal of Molecular Sciences},
  volume    = {22},
  journal   = {International Journal of Molecular Sciences},
  number    = {6},
  issn      = {1422-0067},
  doi       = {10.3390/ijms22063039},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259198},
  year      = {2021},
  abstract  = {Since Otto Warburg reported in 1924 that cancer cells address their increased energy requirement through a massive intake of glucose, the cellular energy level has offered a therapeutic anticancer strategy. Methionine restriction (MetR) is one of the most effective approaches for inducing low-energy metabolism (LEM) due to the central position in metabolism of this amino acid. However, no simple in vitro system for the rapid analysis of MetR is currently available, and this study establishes the murine cell line L929 as such a model system. L929 cells react rapidly and efficiently to MetR, and the analysis of more than 150 different metabolites belonging to different classes (amino acids, urea and tricarboxylic acid cycle (TCA) cycles, carbohydrates, etc.) by liquid chromatography/mass spectrometry (LC/MS) defines a metabolic fingerprint and enables the identification of specific metabolites representing normal or MetR conditions. The system facilitates the rapid and efficient testing of potential cancer therapeutic metabolic targets. To date, MS studies of MetR have been performed using organisms and yeast, and the current LC/MS analysis of the intra- and extracellular metabolites in the murine cell line L929 over a period of 5 days thus provides new insights into the effects of MetR at the cellular metabolic level.},
  language  = {en}
}
@article{SchmitzRiesKodereretal.2021,
  author    = {Schmitz, Werner and Ries, Elena and Koderer, Corinna and V{\"o}lter, Maximilian Friedrich and W{\"u}nsch, Anna Chiara and El-Mesery, Mohamed and Frackmann, Kyra and K{\"u}bler, Alexander Christian and Linz, Christian and Seher, Axel},
  title     = {Cysteine restriction in murine L929 fibroblasts as an alternative strategy to methionine restriction in cancer therapy},
  series = {International Journal of Molecular Sciences},
  volume    = {22},
  journal   = {International Journal of Molecular Sciences},
  number    = {21},
  issn      = {1422-0067},
  doi       = {10.3390/ijms222111630},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265486},
  year      = {2021},
  abstract  = {Methionine restriction (MetR) is an efficient method of amino acid restriction (AR) in cells and organisms that induces low energy metabolism (LEM) similar to caloric restriction (CR). The implementation of MetR as a therapy for cancer or other diseases is not simple since the elimination of a single amino acid in the diet is difficult. However, the in vivo turnover rate of cysteine is usually higher than the rate of intake through food. For this reason, every cell can enzymatically synthesize cysteine from methionine, which enables the use of specific enzymatic inhibitors. In this work, we analysed the potential of cysteine restriction (CysR) in the murine cell line L929. This study determined metabolic fingerprints using mass spectrometry (LC/MS). The profiles were compared with profiles created in an earlier work under MetR. The study was supplemented by proliferation studies using D-amino acid analogues and inhibitors of intracellular cysteine synthesis. CysR showed a proliferation inhibition potential comparable to that of MetR. However, the metabolic footprints differed significantly and showed that CysR does not induce classic LEM at the metabolic level. Nevertheless, CysR offers great potential as an alternative for decisive interventions in general and tumour metabolism at the metabolic level.},
  language  = {en}
}
@article{WuenschRiesHeinzelmannetal.2023,
  author    = {W{\"u}nsch, Anna Chiara and Ries, Elena and Heinzelmann, Sina and Frabschka, Andrea and Wagner, Peter Christoph and Rauch, Theresa and Koderer, Corinna and El-Mesery, Mohamed and Volland, Julian Manuel and K{\"u}bler, Alexander Christian and Hartmann, Stefan and Seher, Axel},
  title     = {Metabolic silencing via methionine-based amino acid restriction in head and neck cancer},
  series = {Current Issues in Molecular Biology},
  volume    = {45},
  journal   = {Current Issues in Molecular Biology},
  number    = {6},
  issn      = {1467-3045},
  doi       = {10.3390/cimb45060289},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319257},
  pages     = {4557 -- 4573},
  year      = {2023},
  abstract  = {In recent years, various forms of caloric restriction (CR) and amino acid or protein restriction (AAR or PR) have shown not only success in preventing age-associated diseases, such as type II diabetes and cardiovascular diseases, but also potential for cancer therapy. These strategies not only reprogram metabolism to low-energy metabolism (LEM), which is disadvantageous for neoplastic cells, but also significantly inhibit proliferation. Head and neck squamous cell carcinoma (HNSCC) is one of the most common tumour types, with over 600,000 new cases diagnosed annually worldwide. With a 5-year survival rate of approximately 55\%, the poor prognosis has not improved despite extensive research and new adjuvant therapies. Therefore, for the first time, we analysed the potential of methionine restriction (MetR) in selected HNSCC cell lines. We investigated the influence of MetR on cell proliferation and vitality, the compensation for MetR by homocysteine, the gene regulation of different amino acid transporters, and the influence of cisplatin on cell proliferation in different HNSCC cell lines.},
  language  = {en}
}