The Mitochondrial Citrate Carrier (SLC25A1) Sustains Redox Homeostasis and Mitochondrial Metabolism Supporting Radioresistance of Cancer Cells With Tolerance to Cycling Severe Hypoxia

Abstract

Pronounced resistance of lung cancer cells to radiotherapy and chemotherapy is a major barrier to successful treatment. Herein, both tumor hypoxia and the upregulation of the cellular antioxidant defense systems observed during malignant progression can contribute to radioresistance. We recently found that exposure to chronic cycling severe hypoxia/reoxygenation stress results in glutamine-dependent upregulation of cellular glutathione (GSH) levels and associated radiation resistance opening novel routes for tumor cell-specific radiosensitization. Here, we explored the role of the mitochondrial citrate carrier (SLC25A1) for the improved antioxidant defense of cancer cells with tolerance to acute and chronic severe hypoxia/reoxygenation stress and the use of pharmacologic SLC25A1 inhibition for tumor cell radiosensitization. Exposure to acute or chronic cycling severe hypoxia/reoxygenation stress triggered upregulated expression of SLC25A1 in lung cancer, prostate cancer, and glioblastoma cells in vitro. Interestingly, exposure to ionizing radiation (IR) further promoted SLC25A1 expression. Inhibition of SLC25A1 by 1,2,3-benzene-tricarboxylic acid (BTA) disturbed cellular and mitochondrial redox homeostasis, lowered mitochondrial metabolism, and reduced metabolic flexibility of cancer cells. Even more important, combining IR with BTA was able to overcome increased radioresistance induced by adaptation to chronic cycling severe hypoxia/reoxygenation stress. This radiosensitizing effect of BTA-treated cells was linked to increased reactive oxygen species and reduced DNA repair capacity. Of note, key findings could be reproduced when using the SLC25A1-inhibitor 4-Chloro-3-[[(3-nitrophenyl)amino]sulfonyl]-benzoic acid (CNASB). Moreover, in silico analysis of publically available databases applying the Kaplan–Meier plotter tool () revealed that overexpression of SLC25A1 was associated with reduced survival of lung cancer patients suggesting a potential link to aggressive cancers. We show that SLC25A1 can contribute to the increased antioxidant defense of cancer cells allowing them to escape the cytotoxic effects of IR. Since upregulation of SLC25A1 is induced by adverse conditions in the tumor environment, exposure to IR, or both pharmacologic inhibition of SLC25A1 might be an effective strategy for radiosensitization of cancer cells particularly in chronically hypoxic tumor fractions.

Spatial modeling of prostate cancer metabolic gene expression reveals extensive heterogeneity and selective vulnerabilities

“…3D). Our model's prediction of SLC25A1's essentiality in hypoxic tumor cells is substantiated by prior findings that SLC25A1 expression is up-regulated when prostate cancer cells are exposed to cycling hypoxia/re-oxygenation stress 74 . Notably, pharmacological inhibition of SLC25A1 sensitizes cancer cells to ionizing radiation, cisplatin or EGFR inhibitor treatments in lung cancer 74,75 .…”

“…Our model's prediction of SLC25A1's essentiality in hypoxic tumor cells is substantiated by prior findings that SLC25A1 expression is up-regulated when prostate cancer cells are exposed to cycling hypoxia/re-oxygenation stress 74 . Notably, pharmacological inhibition of SLC25A1 sensitizes cancer cells to ionizing radiation, cisplatin or EGFR inhibitor treatments in lung cancer 74,75 . Thus, treating prostate cancer cells in a hypoxic TME with the SLC25A1 inhibitor, 1,2,3-benzene-tricarboxylic acid (BTA) could not only yield direct tumor-specific killing, but it could also potentiate the activity of concomitant radiation or chemotherapy interventions.…”

Patient Adipose Stem Cell-Derived Adipocytes Reveal Genetic Variation that Predicts Antidiabetic Drug Response

“…Similarly, as SLC25A1 encodes a citrate transporter that is important for mitochondrial metabolism (Hlouschek et al, 2018), we also examined whether the effect of rosi on the mitochondrial function of patient-derived adipocytes was differentially affected by the rs2106146 genotype. Indeed, the G/Gpatient-derived adipocytes with reduced PPARg binding and rosi induction of SLC25A1 exhibited an impaired effect of rosi on both basal ( Figure S4F) and maximal mitochondrial respiration ( Figure S4G).…”

Targeting the Mitochondrial Metabolic Network: A Promising Strategy in Cancer Treatment

“…Among these, a key intermediate is citrate, which exits the mitochondria and supplies the cytosolic environment with the acetyl-CoA necessary for fatty-acid and cholesterol biosynthesis, as well as for gene expression regulation at the epigenetic level (histone acetylation). In this regard, the importance of the mitochondrial citrate carrier (SLC25A1) has recently emerged in tumor progression, cancer stemness, and resistance to therapy; additionally, the specific SLC25A1 inhibitor benzenetricarboxylate (BTA) has been proven to exert a promising anticancer activity [ 8 , 9 , 10 ].…”