α-ketoglutarate dehydrogenase inhibition counteracts breast cancer-associated lung metastasis

Abstract

Metastasis formation requires active energy production and is regulated at multiple levels by mitochondrial metabolism. The hyperactive metabolism of cancer cells supports their extreme adaptability and plasticity and facilitates resistance to common anticancer therapies. In spite the potential relevance of a metastasis metabolic control therapy, so far, limited experience is available in this direction. Here, we evaluated the effect of the recently described α-ketoglutarate dehydrogenase (KGDH) inhibitor, (S)-2-[(2,6-dichlorobenzoyl) amino] succinic acid (AA6), in an orthotopic mouse model of breast cancer 4T1 and in other human breast cancer cell lines. In all conditions, AA6 altered Krebs cycle causing intracellular α-ketoglutarate (α-KG) accumulation. Consequently, the activity of the α-KG-dependent epigenetic enzymes, including the DNA demethylation ten-eleven translocation translocation hydroxylases (TETs), was increased. In mice, AA6 injection reduced metastasis formation and increased 5hmC levels in primary tumours. Moreover, in vitro and in vivo treatment with AA6 determined an α-KG accumulation paralleled by an enhanced production of nitric oxide (NO). This epigenetically remodelled metabolic environment efficiently counteracted the initiating steps of tumour invasion inhibiting the epithelial-to-mesenchymal transition (EMT). Mechanistically, AA6 treatment could be linked to upregulation of the NO-sensitive anti-metastatic miRNA 200 family and down-modulation of EMT-associated transcription factor Zeb1 and its CtBP1 cofactor. This scenario led to a decrease of the matrix metalloproteinase 3 (MMP3) and to an impairment of 4T1 aggressiveness. Overall, our data suggest that AA6 determines an α-KG-dependent epigenetic regulation of the TET–miR200–Zeb1/CtBP1–MMP3 axis providing an anti-metastatic effect in a mouse model of breast cancer-associated metastasis.

Metabolic rewiring in the promotion of cancer metastasis: mechanisms and therapeutic implications

“…Up-regulation of α-KG dehydrogenase in breast cancer confers oncogenic properties as it diminished α-KG levels. Conversely, inhibition of this enzyme mediate α-KG accumulation to suppress tumor progression and metastasis in p53 −/− pancreatic ductal adenocarcinoma and breast cancer [21,22]. Mechanistically, α-KG promotes TETs-mediated promoter demethylation and re-expression of antimetastatic miR-200 cluster, thereby down-regulating ZEB1/CtBP1-MMP3 axis and EMT phenotype [22].…”

“…Conversely, inhibition of this enzyme mediate α-KG accumulation to suppress tumor progression and metastasis in p53 −/− pancreatic ductal adenocarcinoma and breast cancer [21,22]. Mechanistically, α-KG promotes TETs-mediated promoter demethylation and re-expression of antimetastatic miR-200 cluster, thereby down-regulating ZEB1/CtBP1-MMP3 axis and EMT phenotype [22]. Collectively, these studies highlight the α-KG-to-succinate/fumarate/2-HG ratios as pivotal regulators of EMT phenotype and metastasis in multiple cancer types.…”

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

“…Increasing the α‐ketoglutarate levels in the cell, is challenging. In a recent mouse model study of breast cancer, the α‐ketoglutarate dehydrogenase (KGDH) inhibitor (AA6) was able to cause intracellular α‐ketoglutarate accumulation …”

Complex Mitochondrial Dysfunction Induced by TPP+-Gentisic Acid and Mitochondrial Translation Inhibition by Doxycycline Evokes Synergistic Lethality in Breast Cancer Cells

“…In BC, mitochondrial metabolism has been recognized as an essential factor that promotes metastasis [1,4,47], drug resistance [48][49][50], survival and propagation of cancer stem cells (CSCs) and tumor-initiating cells (TICs) [51,52], making it a promising target for new anticancer approaches.…”