https://scholars.lib.ntu.edu.tw/handle/123456789/478373
標題: | Transketolase Regulates the Metabolic Switch to Control Breast Cancer Cell Metastasis via the a-Ketoglutarate Signaling Pathway | 作者: | Tseng C.-W. WEN-HUNG KUO Chan S.-H. Chan H.-L. KING-JEN CHANG Wang L.-H. |
公開日期: | 2018 | 出版社: | American Association for Cancer Research Inc. | 卷: | 78 | 期: | 11 | 起(迄)頁: | 2799-2812 | 來源出版物: | Cancer Research | 摘要: | 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 (aKG) 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 HIF1a, ultimately suppressing breast cancer metastasis. Reduced TKT or addition of aKG 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 aKG in TNBC cells. Together, our study has identified a novel TKT-mediated aKG 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 aKG. ? 2018 American Association for Cancer Research. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85048040586&doi=10.1158%2f0008-5472.CAN-17-2906&partnerID=40&md5=1a76977380ed2aa6acd74202af2a515c https://scholars.lib.ntu.edu.tw/handle/123456789/478373 |
ISSN: | 0008-5472 | DOI: | 10.1158/0008-5472.CAN-17-2906 | SDG/關鍵字: | 2 oxoglutaric acid; docetaxel; doxorubicin; fumarate hydratase; hypoxia inducible factor 1alpha; hypoxia inducible factor proline dioxygenase; oxythiamine; transketolase; 2 oxoglutaric acid; fumarate hydratase; hypoxia inducible factor 1alpha; transketolase; alpha ketoglutarate signaling; animal experiment; animal model; animal tissue; Article; breast cancer; breast carcinogenesis; cancer growth; cancer survival; cell cycle progression; cell death; cell migration; cell proliferation; controlled study; down regulation; female; glucose metabolism; glycolysis; human; human cell; immunohistochemistry; lung metastasis; lymph node metastasis; matrix-assisted laser desorption-ionization mass spectrometry; metastasis inhibition; mitochondrial respiration; mouse; nonhuman; oxidative phosphorylation; priority journal; protein analysis; protein depletion; protein expression; protein function; regulatory mechanism; signal transduction; survival rate; triple negative breast cancer; tumor invasion; tumor volume; Western blotting; animal; Bagg albino mouse; MCF-7 cell line; metabolism; metastasis; pathology; physiology; SCID mouse; signal transduction; tumor cell line; Animals; Cell Line, Tumor; Female; Fumarate Hydratase; Glycolysis; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Ketoglutaric Acids; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, SCID; Neoplasm Metastasis; Oxidative Phosphorylation; Signal Transduction; Transketolase; Triple Negative Breast Neoplasms |
顯示於: | 醫學系 |
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