Blockage Of Glycolysis By Targeting PFKFB3 Suppresses Tumor Growth And Metastasis In Head And Neck Squamous Cell Carcinoma

Objective:Many cancers including head and neck squamous carcinoma(HNSCC)exhibit a special metabolic rewiring characterized with increased glucose uptake and lactate production,termed as aerobic glycolysis.By targeting PFKFB3,a glucose metabolizing enzyme,this study aims to investigate the therapeutic potential of glycolysis blockage in HNSCC.Methods:1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-l-one(PFK15)was introduced as a selective antagonist of PFKFB3.Glycolytic flux was measured by detecting glucose uptake,lactate production and the ATP yield.PFKFB3 expression was examined by IHC.Cell cycle,proliferation,apoptosis and motility were also analysed,HNSCC xenograft mice model and metastasis mice model were established to determine the therapeutic efficacy of PFK15 in vivo.Results:HNSCC showed a higher PFKFB3 expression compared with adjacent normal tissues.Targeting PFKFB3 significantly reduced glycolytic flux in HNSCC cell lines.PFK15 evidently inhibited cell proliferation,blocked cell cycle progression and induced apoptosis.The invadopodia formation of HNSCC cells was markedly suppressed after PFK15 treatment,thereby reducing cell motility and ECM(extra cellular matrix)degradation ability.The in vivo data of the xenograft and metastatic mice models proved that PFK15 administration apparently suppressed tumor growth,alleviated the lung metastasis and potentially extended the life expectancy of mice.Conclusions:The pharmacological blockage of PFKFB3 via PFK15 suppressed HNSCC growth and metastasis,thus offering a promising strategy for cancer therapy.