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.Significance: 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. Cancer Res; 78(11); 2799-812. ©2018 AACR.
Highlights
Patients with breast cancer have a 5-year survival rate over 90%; for patients with distant metastasis, their survival rate decreases to only about 25% because of the lack of effective strategies against breast cancer metastasis and recurrence [1]
Three proteins related to glycolysis were upregulated in the bigger tumors; they included aldolase A (ALDOA), triose phosphate isomerase (TPIS), and ENOA
These results indicate that TKT depletion enhances L-2HG dehydrogenase (L2HGDH) and D-2HG dehydrogenase (D2HGDH) levels, resulting in the increase of aKG and prolyl hydroxylase 2 (PHD2) levels and thereby promoting HIF1a degradation
Summary
Patients with breast cancer have a 5-year survival rate over 90%; for patients with distant metastasis, their survival rate decreases to only about 25% because of the lack of effective strategies against breast cancer metastasis and recurrence [1]. Tumor cells with altered metabolic program have high requirements of glucose metabolism for rapid proliferation. Despite some studies aiming at elucidating the correlation between aberrant metabolic behavior and tumor progression, how metabolic processes regulate breast cancer cells growth and metastasis is not fully understood. A number of studies show that oncogenic signaling in cancers drives metabolic reprogramming to generate large amounts of biomass during rapid tumor growth [2]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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