Lehrstuhl für Physiologische Chemie

    Identification of novel targets: The cysteine metabolism in melanoma development and maintenance

    Reactive oxygen species (ROS) signaling plays a crucial role for tumor development in melanoma, as e.g. shown for the example of tumor angiogenesis in fish melanoma (Schaafhausen et al., J Cell Sci, 2013). However, melanoma development goes along with high expression of antioxidants (Lokaj et al., J Proteome Res., 2009) and there is a delicate balance between pro- and antioxidant events in melanoma (reviewed in Meierjohann, Eur J Cell Biol, 2014). RTKs are a strong ROS promoter, and this can lead to the induction of senescence if not counteracted. In vitro, high levels of an oncogenic EGF receptor inevitably lead to senescence and cellular arrest, mediated by the DNA damage pathway. We observe the same phenomenon when we express human NRASQ61K in melanocytes (Leikam et al., Oncogene, 2008). To prevent senescence and allow tumor propagation, there exist a number of potential antioxidant strategies. We could show that the oncogene MYC prevents ROS-induced senescence by activating the cystathionase (CTH) gene, which is an enzyme of the transsulfuration pathway and is involved in regenerating the intracellular redox-buffer cysteine. Importantly, melanoma cells are still dependent on CTH, as pharmacological or siRNA-mediated inhibition of CTH drives the large majority of human melanoma cells into senescence or apoptosis (Figure 3) (Leikam et al., Oncogene, 2014). In comparison, normal human epidermal melanocytes (NHEM) do not require CTH activity.

    Figure 3: Schematic overview of the cysteine supply by the transsulfuration pathway (TSP) and its efffect on cellular antioxidants. The TSP generates cysteine (Cys) from methionine (Met), with CTH being the last enzyme in the pathway CTH: cystathionase, ROS: reactive oxygen species

    These data indicate that established melanomas depend on a strong cysteine supply much more than untransformed cells, thus revealing a possible „Achilles heel“ of the tumors. Currently, we are optimizing inhibition of the cysteine metabolism using in vitro and in vivo melanoma models.

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