Abstract
Since it is known that cancer cells exhibit a preference for increased glycine consumption, the respective glycine metabolizing enzymes are in focus of many research projects. However, no cancer associated studies are available for the Glycine Cleavage System Protein H (GCSH) to date. Our initial analysis revealed a GCSH-overexpression of the protein-coding transcript variant 1 (Tv1) in breast cancer cells and tissue. Furthermore, a shorter (391 bp) transcript variant (Tv*) was amplified with an increased expression in healthy breast cells and a decreased expression in breast cancer samples. The Tv1/Tv* transcript ratio is 1.0 in healthy cells on average, and between 5–10 in breast cancer cells. Thus, a GCSH-equilibrium at the transcript level is likely conceivable for optimal glycine degradation. A possible regulative role of Tv* was proven by Tv1-Tv*-RNA-binding and overexpression studies which consequently led to serious physiological alterations: decreased metabolic activity, release of the lactate dehydrogenase, increased extracellular acidification, and finally necrosis as a result of impaired plasma membranes. In contrast, Tv1-overexpression led to an additional increase in cellular vitality of the tumor cells, primarily due to the acceleration of the mitochondrial glycine decarboxylation activity. Ultimately, we provide the first evidence of a sensitive GCSH-antisense regulation which determines cancerous cell viability.
Highlights
Glycine metabolism, the glycine-to-serine conversion by the glycine decarboxylase (GLDC) and the three other proteins of the glycine cleavage system (GCS), in conjunction with serine hydroxymethyltransferase (SHMT), are functionally associated with one-carbon (C1)-metabolism for the generation of purines in most organisms
Glycine Cleavage System Protein H (GCSH) protein is overexpressed in both, breast cancer tissue and breast cancer cell lines
To evaluate GCSH expression in vivo as well as in vitro, paraffin-embedded normal breast and breast cancer tissue (Fig. 1A,B) as well as three commercially available breast cancer cell lines (MCF-7, MDA-MB-231 and BT-20; Fig. 1C) in comparison with non-tumorigenic controls were immunolabeled with a monoclonal, full length GCSH-specific antibody
Summary
The glycine-to-serine conversion by the glycine decarboxylase (GLDC) and the three other proteins of the glycine cleavage system (GCS), in conjunction with serine hydroxymethyltransferase (SHMT), are functionally associated with one-carbon (C1)-metabolism for the generation of purines in most organisms. Results GCSH protein is overexpressed in both, breast cancer tissue and breast cancer cell lines. A GCSH-overexpression could be confirmed for the breast cancer cell lines MCF-7 and BT-20.
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