Metabolic induction of DNA repair defects for improving the outcome of radiotherapy.
Final Report Abstract
This project explored the role of the mitochondrial citrate transporter SLC25A1 in enhancing cancer cell radiosensitivity by modulating their metabolism and DNA repair processes. The effectiveness of radiotherapy is often limited by tumor resistance, as cancer cells balance redox homeostasis and energy metabolism to ensure DNA repair and survival after exposure to chemotherapy or radiotherapy. Our previous work demonstrated that adaptive changes in antioxidant defense and cancer cell metabolism not only enhance radioresistance but also create metabolic dependencies that can be targeted to overcome this resistance. The proposed project aimed to identify additional metabolic dependencies that impact the ability of cancer cells to repair radiation-induced DNA lesions, with the goal of defining tumorspecific therapeutic targets to increase radiosensitivity and improve patient outcomes in combinatorial treatments. Key findings confirmed that SLC25A1 inhibition (SLC25A1i) leads to the accumulation of 2-hydroxyglutarate (2HG), impairing homologous recombination repair (HRR) and enhancing the effects of radiotherapy when combined with DNA repair inhibitors like PARP inhibitors. Furthermore, cancer cells were shown to undergo a common transient mitochondrial shutdown in response to ionizing radiation, revealing a potential vulnerability for therapeutic exploitation. The study also emphasized the importance of metabolic reprogramming in enhancing radiosensitivity, particularly through the supplementation of αketoglutarate, and highlighted the role of nicotinamide dinucleotide (NAD) in modulating this response. The conclusions suggest that SLC25A1i could serve as a promising target for druginduced context-dependent lethality following irradiation. A deeper understanding of cancer metabolism, particularly the role of NAD metabolism in these processes, is crucial for developing more effective radiotherapy strategies. Ongoing metabolomic analyses aim to further elucidate these mechanisms, potentially leading to more effective radiotherapy strategies in resistant tumors.
Publications
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Metabolism of cancer cells commonly responds to irradiation by a transient early mitochondrial shutdown. iScience, 24(11), 103366.
Krysztofiak, Adam; Szymonowicz, Klaudia; Hlouschek, Julian; Xiang, Kexu; Waterkamp, Christoph; Larafa, Safa; Goetting, Isabell; Vega-Rubin-de-Celis, Silvia; Theiss, Carsten; Matschke, Veronika; Hoffmann, Daniel; Jendrossek, Verena & Matschke, Johann
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Accumulation of oncometabolite D-2-Hydroxyglutarate by SLC25A1 inhibition: A metabolic strategy for induction of HR-ness and radiosensitivity. Cell Death & Disease, 13(7).
Xiang, Kexu; Kalthoff, Christian; Münch, Corinna; Jendrossek, Verena & Matschke, Johann
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α-Ketoglutarate supplementation and NAD+ modulation enhance metabolic rewiring and radiosensitization in SLC25A1 inhibited cancer cells. Cell Death Discovery, 10(1).
Xiang, Kexu; Kunin, Mikhail; Larafa, Safa; Busch, Maike; Dünker, Nicole; Jendrossek, Verena & Matschke, Johann
