α-Ketoglutarate Supplementation and NAD+ Modulation Enhance Metabolic Rewiring and Radiosensitization in SLC25A1 Inhibited Cancer Cells

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Metabolic rewiring is the result of the growing demands and proliferation of cancer cells, leading to alterations of biological activities and reactions to treatments of cancer cells. The mitochondrial citrate transport protein SLC25A1 is involved in metabolic reprogramming offering a strategy to induce metabolic bottlenecks with relevance for radiosensitization by accumulation of the oncometabolite D-2-hydroxyglutarate (D-2HG) upon SLC25A1 inhibition (SLC25A1i). Previous studies have uncovered the comparative effects of SLC25A1i or cell permeable D-2HG (octyl-D-2HG) treatments on DNA damage induction and repair as well as on energy metabolism and cellular function crucial for long-term survival of irradiated cells. Here, α-ketoglutarate (αKG), the precursor of D-2HG, potentiated the effects observed upon SLC25A1i on DNA damage repair, cell function and long-term survival in vitro and in vivo, thus making NCI-H460 cancer cells more vulnerable to ionizing radiation. However, αKG treatment alone could hardly exert its effect on the respective phenotypes. Additionally, nicotinamide (NAM) supplementation, as the precursor of NAD (including NAD+ and NADH), was counteracting the effects of SLC25A1i or the combination of SLC25A1i with αKG, emphasizing a potential importance of NAD+/NADH equilibrium on cellular activities relevant for survival of irradiated cancer cells upon SLC25A1i. Furthermore, inhibition of histone lysine demethylases (KDMs), as a major factor affected upon SLC25A1i, by JIB04 treatment alone or in combination with αKG supplementation phenocopied the wide-ranging effects on mitochondrial and cellular function induced upon SLC25A1i. Collectively, αKG-supplementation potentiated the effects on cellular processes observed upon SLC25A1i and increased cellular need for NAD to re-balance the cellular state and ensure survival upon irradiation. Future studies will uncover the underlying metabolic reprogramming induced by SLC25A1i offering novel therapeutic strategies for cancer treatment.