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.