Determination of Pyruvate Metabolic Fates Modulates Head and Neck Tumorigenesis

Tsai Ying Chen, Yi Ta Hsieh, Jian Min Huang, Chung Ji Liu, Lu Te Chuang, Pei Chun Huang, Tz Yu Kuo, Hao Yuan Chia, Chia Yi Chou, Ching Wen Chang, Yi Fen Chen, Hsin Ming Chen, Jeng Fan Lo, Wan Chun Li*

*此作品的通信作者

研究成果: Article同行評審

21 引文 斯高帕斯(Scopus)

摘要

Even with increasing evidence for roles of glycolytic enzymes in controlling cancerous characteristics, the best target of candidate metabolic enzymes for lessening malignancy remains under debate. Pyruvate is a main glycolytic metabolite that could be mainly converted into either lactate by Lactate Dehydrogenase A (LDHA)or acetyl-CoA by Pyruvate Dehydrogenase E1 component α subunit (PDHA1)catalytic complex. In tumor cells, accumulating lactate is produced whereas the conversion of pyruvate into mitochondrial acetyl-CoA is less active compared with their normal counterparts. This reciprocal molecular association makes pyruvate metabolism a potential choice of anti-cancer target. Cellular and molecular changes were herein assayed in Head and Neck Squamous Cell Carcinoma (HNSCC)cells in response to LDHA and PDHA1 loss in vitro, in vivo and in clinic. By using various human cancer databases and clinical samples, LDHA and PDHA1 levels exhibit reversed prognostic roles. In vitro analysis demonstrated that decreased cell growth and motility accompanied by an increased sensitivity to chemotherapeutic agents was found in cells with LDHA loss whereas PDHA1-silencing exhibited opposite phenotypes. At the molecular level, it was found that oncogenic Protein kinase B (PKB/Akt)and Extracellular signal-regulated kinase (ERK)singling pathways contribute to pyruvate metabolism mediated HNSCC cell growth. Furthermore, LDHA/PDHA1 changes in HNSCC cells resulted in a broad metabolic reprogramming while intracellular molecules including polyunsaturated fatty acids and nitrogen metabolism related metabolites underlie the malignant changes. Collectively, our findings reveal the significance of pyruvate metabolic fates in modulating HNSCC tumorigenesis and highlight the impact of metabolic plasticity in HNSCC cells.

原文English
頁(從 - 到)641-652
頁數12
期刊Neoplasia
21
發行號7
DOIs
出版狀態Published - 7月 2019

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