Blockage of glycolysis by targeting PFKFB3 suppresses tumor growth and metastasis in head and neck squamous cell carcinoma.
Blockage of glycolysis by targeting PFKFB3 suppresses tumor growth and metastasis in head and neck squamous cell carcinoma.
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通过靶向 PFKFB3 阻断糖酵解可抑制头颈鳞状细胞癌的肿瘤生长和转移
DOI：
10.1186/s13046-016-0481-1
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发表时间：
2017-01-07
期刊：
影响因子：
--
通讯作者：
Jia J
中科院分区：
文献类型：
--
作者：
Li HM;Yang JG;Liu ZJ;Wang WM;Yu ZL;Ren JG;Chen G;Zhang W;Jia J
研究背景包括头颈部鳞状细胞癌（HNSCC）在内的许多癌症的特征是代谢重新连接，葡萄糖摄取和乳酸产生增加，称为有氧糖酵解。靶向有氧糖酵解为癌症治疗提供了一种有前途的策略。本研究旨在探讨以磷酸果糖激酶-2/果糖-2，6-二磷酸酶3（PFKFB 3）为靶点阻断糖酵解对HNSCC的治疗作用。通过测量葡萄糖摄取、乳酸产生和ATP产率来确定糖酵解通量。使用HNSCC组织阵列检查PFKFB 3表达。分析细胞增殖、凋亡和运动能力。结果与癌旁组织相比，HNSCC中PFKFB 3的表达明显增加（P <0. 0 1），而癌旁组织中PFKFB 3的表达明显增加（P<0. 0 1）。通过PFK 15靶向PFKFB 3显著降低了HNSCC细胞系中的葡萄糖摄取、乳酸产生和ATP产生。PFK 15抑制细胞增殖，停止细胞周期进程，并诱导细胞凋亡。PFK 15处理后HNSCC细胞的侵袭足明显减少，从而损害细胞运动和细胞外基质降解能力。来自异种移植小鼠模型的体内数据证明PFK 15施用抑制肿瘤生长。结论PFKFB 3通过PFK 15的药理学抑制作用抑制了HNSCC的生长，减轻了肿瘤的转移，为肿瘤的治疗提供了一种有前景的策略。
BackgroundMany 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.Methods1-(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.ResultsHNSCC showed an increased PFKFB3 expression compared with adjacent mucosal tissues (P< 0.01). Targeting PFKFB3viaPFK15 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.ConclusionsThe pharmacological inhibition of PFKFB3viaPFK15 suppressed tumor growth and alleviated metastasis in HNSCC, offering a promising strategy for cancer therapy.
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影响因子：
64.5
作者：
De Bock, Katrien;Georgiadou, Maria;Carmeliet, Peter
通讯作者：
Carmeliet, Peter
影响因子：
9.7
作者：
Lu, Jianrong;Tan, Ming;Cai, Qingsong
通讯作者：
Cai, Qingsong
影响因子：
4.6
作者：
Chen L;Zhao J;Tang Q;Li H;Zhang C;Yu R;Zhao Y;Huo Y;Wu C
通讯作者：
Wu C
影响因子：
168.9
作者：
Ashrafian, H
通讯作者：
Ashrafian, H
DOI：
10.1073/pnas.96.6.3047
发表时间：
1999-03-16
影响因子：
11.1
作者：
Chesney, J;Mitchell, R;Bucala, R
通讯作者：
Bucala, R