TY - JOUR A1 - Koderer, Corinna A1 - Schmitz, Werner A1 - Wünsch, Anna Chiara A1 - Balint, Julia A1 - El-Mesery, Mohamed A1 - Volland, Julian Manuel A1 - Hartmann, Stefan A1 - Linz, Christian A1 - Kübler, Alexander Christian A1 - Seher, Axel T1 - Low energy status under methionine restriction is essentially independent of proliferation or cell contact inhibition JF - Cells N2 - 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. KW - methionine restriction KW - caloric restriction KW - mass spectrometry KW - LC/MS KW - liquid chromatography/mass spectrometry KW - metabolomics KW - L929 KW - amino acid KW - proliferation KW - contact inhibition Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262329 SN - 2073-4409 VL - 11 IS - 3 ER - TY - JOUR A1 - Schmitz, Werner A1 - Ries, Elena A1 - Koderer, Corinna A1 - Völter, Maximilian Friedrich A1 - Wünsch, Anna Chiara A1 - El-Mesery, Mohamed A1 - Frackmann, Kyra A1 - Kübler, Alexander Christian A1 - Linz, Christian A1 - Seher, Axel T1 - Cysteine restriction in murine L929 fibroblasts as an alternative strategy to methionine restriction in cancer therapy JF - International Journal of Molecular Sciences N2 - 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. KW - methionine restriction KW - cysteine restriction KW - mass spectrometry KW - LC/MS KW - cancer therapy KW - caloric restriction KW - homocysteine KW - amino acid analogues KW - cysteine synthase inhibitor Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265486 SN - 1422-0067 VL - 22 IS - 21 ER - TY - JOUR A1 - Boschert, Verena A1 - Klenk, Nicola A1 - Abt, Alexander A1 - Raman, Sudha Janaki A1 - Fischer, Markus A1 - Brands, Roman C. A1 - Seher, Axel A1 - Linz, Christian A1 - Müller-Richter, Urs D. A. A1 - Bischler, Thorsten A1 - Hartmann, Stefan T1 - The influence of Met receptor level on HGF-induced glycolytic reprogramming in head and neck squamous cell carcinoma JF - International Journal of Molecular Sciences N2 - Head and neck squamous cell carcinoma (HNSCC) is known to overexpress a variety of receptor tyrosine kinases, such as the HGF receptor Met. Like other malignancies, HNSCC involves a mutual interaction between the tumor cells and surrounding tissues and cells. We hypothesized that activation of HGF/Met signaling in HNSCC influences glucose metabolism and therefore substantially changes the tumor microenvironment. To determine the effect of HGF, we submitted three established HNSCC cell lines to mRNA sequencing. Dynamic changes in glucose metabolism were measured in real time by an extracellular flux analyzer. As expected, the cell lines exhibited different levels of Met and responded differently to HGF stimulation. As confirmed by mRNA sequencing, the level of Met expression was associated with the number of upregulated HGF-dependent genes. Overall, Met stimulation by HGF leads to increased glycolysis, presumably mediated by higher expression of three key enzymes of glycolysis. These effects appear to be stronger in Met\(^{high}\)-expressing HNSCC cells. Collectively, our data support the hypothesized role of HGF/Met signaling in metabolic reprogramming of HNSCC. KW - HNSCC KW - head and neck cancer KW - HGF KW - Met KW - cancer metabolism Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235995 SN - 1422-0067 VL - 21 IS - 2 ER -