title: Blockage of glycolysis by targeting PFKFB3 suppresses tumor growth and metastasis in head and neck squamous cell carcinoma.
abstract: Many cancers including head and neck squamous cell carcinoma (HNSCC) are characterized by a metabolic rewiring with increased glucose uptake and lactate production, termed as aerobic glycolysis. Targeting aerobic glycolysis presents a promising strategy for cancer therapy. This study investigates the therapeutic potential of glycolysis blockage by targeting phosphofructokinase-2/fructose-2, 6-bisphosphatase 3 (PFKFB3) in HNSCC.
  
  
  
  1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PFK15) was used as a selective antagonist of PFKFB3. Glycolytic flux was determined by measuring glucose uptake, lactate production and ATP yield. PFKFB3 expression was examined using HNSCC tissue arrays. Cell proliferation, apoptosis and motility were analysed. HNSCC xenograft mouse model and metastasis mouse model were established to examine the therapeutic efficacy of PFK15 in vivo.
  
  
  
  HNSCC showed an increased PFKFB3 expression compared with adjacent mucosal tissues (P < 0.01). Targeting PFKFB3 via PFK15 significantly reduced the glucose uptake, lactate production and ATP generation in HNSCC cell lines. PFK15 suppressed cell proliferation, halted cell cycle progression and induced cell apoptosis. The invadopodia of HNSCC cells was markedly reduced after PFK15 treatment, thereby impairing cell motility and extracellular matrix degradation ability. The in vivo data from the xenograft mice models proved that PFK15 administration suppressed the tumor growth. And the results from the metastatic mice models showed administration of PFK15 alleviated the lung metastasis of HNSCC and extended the life expectancy of mice.
  
  
  
  The pharmacological inhibition of PFKFB3 via PFK15 suppressed tumor growth and alleviated metastasis in HNSCC, offering a promising strategy for cancer therapy.
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, 430079, China.
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Li
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, 430079, China.
authors.forename: Jie-Gang
authors.initials: JG
authors.lastname: Yang
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, 430079, China.
authors.forename: Zhuo-Jue
authors.initials: ZJ
authors.lastname: Liu
authors.affiliation: Oral Medical Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410000, China.
authors.forename: Wei-Ming
authors.initials: WM
authors.lastname: Wang
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, 430079, China.
authors.forename: Zi-Li
authors.initials: ZL
authors.lastname: Yu
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, 430079, China.|Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, No237, Luoyu Road, Hongshan District, Wuhan, 430079, China.
authors.forename: Jian-Gang
authors.initials: JG
authors.lastname: Ren
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, 430079, China.|Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, No237, Luoyu Road, Hongshan District, Wuhan, 430079, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, 430079, China. wzhang88@whu.edu.cn.|Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, No237, Luoyu Road, Hongshan District, Wuhan, 430079, China. wzhang88@whu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, 430079, China. junjiaos@sina.com.|Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, No237, Luoyu Road, Hongshan District, Wuhan, 430079, China. junjiaos@sina.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Jia
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D006873:Hydroquinones / Q000008:administration & dosage* / Q000494:pharmacology; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D025481:Phosphofructokinase-2 / Q000037:antagonists & inhibitors*; D000077195:Squamous Cell Carcinoma of Head and Neck; D046888:Tissue Array Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D006873:Hydroquinones; D019344:Lactic Acid; D000255:Adenosine Triphosphate; C107345:PFKFB3 protein, human; D025481:Phosphofructokinase-2
keywords: Glycolysis; HNSCC; Invadopodia; Invasion; Metastasis; PFKFB3