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.

中文翻译：

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丙酮酸代谢命运的测定调节头颈肿瘤的发生。


尽管越来越多的证据表明糖酵解酶在控制癌症特征方面的作用，但候选代谢酶减轻恶性肿瘤的最佳靶标仍然存在争议。丙酮酸是主要的糖酵解代谢物，主要可通过乳酸脱氢酶 A (LDHA) 转化为乳酸，或通过丙酮酸脱氢酶 E1 组分 α 亚基 (PDHA1) 催化复合物转化为乙酰辅酶 A。在肿瘤细胞中，会产生累积的乳酸，而丙酮酸转化为线粒体乙酰辅酶A的活性与正常细胞相比不那么活跃。这种相互的分子关联使丙酮酸代谢成为抗癌靶点的潜在选择。本文在体外、体内和临床中测定了头颈鳞状细胞癌 (HNSCC) 细胞响应 LDHA 和 PDHA1 损失的细胞和分子变化。通过使用各种人类癌症数据库和临床样本，LDHA 和 PDHA1 水平表现出相反的预后作用。体外分析表明，LDHA 缺失的细胞中细胞生长和运动能力下降，同时对化疗药物的敏感性增加，而 PDHA1 沉默则表现出相反的表型。在分子水平上，发现致癌蛋白激酶 B (PKB/Akt) 和细胞外信号调节激酶 (ERK) 信号通路有助于丙酮酸代谢介导的 HNSCC 细胞生长。此外，HNSCC 细胞中 LDHA/PDHA1 的变化导致广泛的代谢重编程，而包括多不饱和脂肪酸和氮代谢相关代谢物在内的细胞内分子是恶性变化的基础。 总的来说，我们的研究结果揭示了丙酮酸代谢命运在调节 HNSCC 肿瘤发生中的重要性，并强调了 HNSCC 细胞代谢可塑性的影响。