Project Details
Projekt
Exploiting ROS defense mechanisms as therapeutic target
Applicant
Professorin Dr. Svenja Meierjohann
Subject Area
Hematology, Oncology
Term
from 2015 to 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 267467939
The cytosol and most compartments inside living cells maintain a reducing environment, which is required for protein function and the prevention of oxidative damage. The maintenance of a functional redox balance is considered an essential process. In most solid cancer types, various oncogenic effectors and the altered metabolic conditions observed in tumors constitute endogenous sources of reactive oxygen species (ROS). Consequently, tumors require strong anti-oxidant measures to counteract the elevated ROS production and ensure survival. Still, ROS levels in cancer cells are usually slightly elevated compared to normal cells. ROS have a dosage-dependent effect: low ROS levels are able to increase pro-tumorigenic signaling. High ROS levels, however, are deleterious to the cells, as they damage DNA, proteins and lipids. It is known that malignant tumor cells are more sensitive to treatment with ROS donors than their healthy counterparts, because their intrinsic ROS levels are already increased. The importance of maintaining the redox balance in tumors opens a therapeutic window which can be exploited for cancer treatment. We demonstrated previously that melanoma cells depend on a strong cysteine supply which is enabled by cysteine de novo synthesis rather than import. We found that the enzyme cystathionase (CTH), which catalyzes cysteine generation from cystathionine, is elevated in melanoma cells in a c-Myc-dependent manner, and pharmacological or siRNA-mediated interference with CTH leads to senescence or apoptosis. This is explained by the antioxidant properties of cysteine and its involvement in glutathione generation. Taken together, our previous work identifies de novo cysteine synthesis as a potential target for tumor treatment. In this project, we will therefore focus on ROS defence mechanisms as therapeutic tumor targets. We will start with the examination of the efficiency of CTH as cancer target in vivo in a mouse melanoma model driven by conditional melanocyte-specific expression of oncogenic BrafV600E and depletion of Pten. In addition, we will use cell lines of this animal model for orthotopic transplantation experiments. The interconnection of cysteine synthesis with other metabolic pathways is also a subject of the project and is planned in collaboration with Z02.To identify further promising targets in the group of proteins involved in antioxidant pathways, we will design a targeted library of inducible shRNA`s in collaboration with Z01. The shRNA pool will be transferred into melanoma cells and investigated for depletion after doxycycline induction. The best targets will be tested in different murine melanoma models and will also be analyzed for potential anti-tumorigenic effects in the other tumor entities represented in the research unit.
DFG Programme
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