C/EBPβ-LIP induced cancer cell metabolism

Cancer cell metabolism nutrient addiction

Prof. dr. C.F. Calkhoven
T. Ackermann

Nature of the research:
Cancer cell metabolism and possible link to cancer therapy

Fields of study:
cell biology oncology molecular biology

Background / introduction
Cancer cells adapt their metabolism to allow for cell growth (mass) and proliferation (number). Typically they maintain a high glycolytic flux (aerobic glycolysis) in order to provide the cell with molecular building blocks for cell growth 1.
During glycolysis NAD+ is reduced to NADH in the redox reactions of glycolysis. To maintain a high glycolytic flux cancer cells need to restore NAD+. Therefore cancer cells convert pyruvate and NADH into lactate and NAD+ (the Warburg effect) 2. Recent publications show a second mechanism by which cancer cells restore NAD+ level. They oxidize the NADH in the mitochondrial electron transport chain. Thereby enable the cell to use pyruvate for synthesis of biomass 3.
Furthermore, NAD+ is an important co-factor in signaling pathways in cancer cells. It is used as a substrate for the polyribosilation of proteins, a protein modification that is part of the cellular stress response. In addition, sirtuins that are key proteins in cellular metabolism and stress response depend on NAD+ as a cofactor 4.
Our research shows that the oncogene C/EBP-LIP induces cancer cell metabolism with a change in NADH/NAD+ utilization and addiction to glucose metabolism. Understanding the relation between C/EBPβ-LIP and NAD+ metabolism may result in novel anti-cancer treatment options.
Research question / problem definition
Therefore, we will to investigate the mechanisms of NADH/NAD+ regulation by LIP in breast cancer cells. Furthermore, we will investigate the role of polyribosilation or sirtuins in LIP-mediated oncogenesis.
As part of the master project the student will learn how to:
- culture and maintain cancer cells
- perform proliferation assays and treat cell with inhibitors of specific pathways
- make protein extracts and analyze them via western blot
- perform metabolic flux analysis via Seahorse XF96 analyser
1. Hanahan D, Weinberg RA., Cell. 2011 Mar 4;144(5):646-74. doi: 10.1016/j.cell.2011.02.013.
2. Vander Heiden et al, Science. 2009 May 22;324(5930):1029-33. doi: 10.1126/science.1160809.
3. Gui et al, Cell Metab. 2016 Nov 8;24(5):716-727. doi: 10.1016/j.cmet.2016.09.006. Epub 2016 Oct 13.
4. Canto et al, Cell Metab. 2015 Jul 7;22(1):31-53. doi: 10.1016/j.cmet.2015.05.023. Epub 2015 Jun 25.
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