Transketolase Regulates the Metabolic Switch to Control Breast Cancer Cell Metastasis via the α-Ketoglutarate Signaling Pathway

Abstract

Although metabolic reprogramming is recognized as a hallmark of tumorigenesis and progression, little is known about metabolic enzymes and oncometabolites that regulate breast cancer metastasis, and very few metabolic molecules have been identified as potential therapeutic targets. In this study, the transketolase (TKT) expression correlated with tumor size in the 4T1/BALB/c syngeneic model. In addition, TKT expression was higher in lymph node metastases compared with primary tumor or normal tissues of patients, and high TKT levels were associated with poor survival. Depletion of TKT or addition of alpha-ketoglutarate (αKG) enhanced the levels of tumor suppressors succinate dehydrogenase and fumarate hydratase (FH), decreasing oncometabolites succinate and fumarate, and further stabilizing HIF prolyl hydroxylase 2 (PHD2) and decreasing HIF1α, ultimately suppressing breast cancer metastasis. Reduced TKT or addition of αKG mediated a dynamic switch of glucose metabolism from glycolysis to oxidative phosphorylation. Various combinations of the TKT inhibitor oxythiamine, docetaxel, and doxorubicin enhanced cell death in triple-negative breast cancer (TNBC) cells. Furthermore, oxythiamine treatment led to increased levels of αKG in TNBC cells. Together, our study has identified a novel TKT-mediated αKG signaling pathway that regulates breast cancer oncogenesis and can be exploited as a modality for improving therapy. These findings uncover the clinical significance of TKT in breast cancer progression and metastasis and demonstrate effective therapy by inhibiting TKT or by adding αKG. .

Identification of a Subtype of Hepatocellular Carcinoma with Poor Prognosis Based on Expression of Genes within the Glucose Metabolic Pathway

“…Besides the upregulated genes in the glycolysis pathway, G6PD and TKT in the pentose phosphate pathway were also consistently upregulated, which predicted worse survival. This is consistent with previous reported functions of these two genes associated with aggressiveness of the disease and drug resistance in other cancer types [54][55][56][57][58]. Most of the genes involved in glycogen metabolism such as GYS2, UGP2, and AGL had down-regulated expression when compared to normal tissues.…”

Modulation of Mitochondrial Metabolic Reprogramming and Oxidative Stress to Overcome Chemoresistance in Cancer

“…Moreover, the reduction of TKT is responsible for a switch from glycolysis to OXPHOS. Consistent with these results, combinations of the TKT inhibitor oxythiamine, docetaxel, and doxorubicin enhance cell death in triple-negative breast cancer cells [57]. In line with these studies, and consistent with what was anticipated in a previous section in this review, we contributed to shedding further light on the correlation between drug resistance and cancer metabolic remodeling through the characterization in several cancer types of the molecular chaperone TRAP1, which has been extensively described for its role in the stress adaptive response of cancer cells, and has recently emerged as a critical regulator of cancer cell metabolism and chemoresistance.…”

“…Catalyzes the phosphorylation of glucose to generate glucose-6-phosphate in the first step of glycolysis. It promotes chemoresistance by enhancing cisplatin-induced autophagy OC [117,118] Transketolase (TKT) Ezyme catalyzing important reaction both in the Calvin cycle and in pentose phosphate pathway BC [57]…”

Crucial role of the pentose phosphate pathway in malignant tumors (Review)

“…In addition, G6PD expression and activity are continuously unregulated in breast cancer cells, and it has been reported that G6PD inhibition leads to an increase in 5'-AMP-activated protein kinase (AMPK) signaling, a decrease in lipid biosynthesis and the inhibition of breast cancer cell growth and survival (21). Furthermore, TKT expression is associated with tumor size in the 4T1/BALB/c syngeneic model, and high TKT levels are associated with poor survival (87).…”