The role of DJ1 (PARK7) in regulating one-carbon metabolism to generate antioxidant capacities in colorectal cancer

• Applicant: Dr. Johannes Meiser
• Subject Area: Gastroenterology ; Biochemistry ; Cell Biology
• Term: from 2016 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 314131633

The major hallmark of cancer is uncontrolled cell proliferation, leading to tumour formation and metastasis. To meet high proliferation rates, cancer cells need profound metabolic reprogramming characterized by a switch from a rather catabolic state towards an anabolic one. Increased metabolic rates also go along with increased reactive oxygen species (ROS) that need to be balanced by the cell to prevent cell death. Cancer cells have been shown to increase their levels of glutathione, the major cellular antioxidant to balance increased levels of ROS. To reduce oxidized glutathione, cells need glutathione peroxidase and the cofactor NADPH. In this context, the folate mediated one carbon metabolism is important for de novo glutathione synthesis and has the ability to generate NADPH, which is needed to recycle oxidised glutathione.DJ-1 (PARK7) has been described as a biomarker in different forms of cancer and to have transforming capacities together with H-RAS. The major role of DJ-1 is to act as a ROS scavenger. Based on publicly available datasets it can be speculated that DJ-1 plays an important role in early tumorigenesis by increasing cellular antioxidant capacities. Based on own previous work, I propose that these increased antioxidant capacities are derived from increased metabolic flux through the folate mediated one-carbon metabolism. With this project I intend to identify key nodes in this metabolic network that are synthetic lethal with DJ-1 upregulation, representing candidate targets for therapy against cancers with high DJ-1 expression.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Alexei Vazquez, Ph.D.