Li Hui-Min, Yang Jie-Gang, Liu Zhuo-Jue, Wang Wei-Ming, Yu Zi-Li, Ren Jian-Gang, Chen Gang, Zhang Wei, Jia Jun
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.
Oral Medical Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410000, China.
J Exp Clin Cancer Res. 2017 Jan 7;36(1):7. doi: 10.1186/s13046-016-0481-1.
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.
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编程，表现为葡萄糖摄取增加和乳酸生成增加，即有氧糖酵解。靶向有氧糖酵解是一种很有前景的癌症治疗策略。本研究探讨了通过靶向磷酸果糖激酶-2/果糖-2,6-二磷酸酶3（PFKFB3）阻断糖酵解在HNSCC中的治疗潜力。
1-(4-吡啶基)-3-(2-喹啉基)-2-丙烯-1-酮（PFK15）用作PFKFB3的选择性拮抗剂。通过测量葡萄糖摄取、乳酸生成和ATP产量来测定糖酵解通量。使用HNSCC组织芯片检测PFKFB3的表达。分析细胞增殖、凋亡和迁移能力。建立HNSCC异种移植小鼠模型和转移小鼠模型，以检测PFK15在体内的治疗效果。
与相邻黏膜组织相比，HNSCC中PFKFB3表达增加（P < 0.01）。通过PFK15靶向PFKFB3可显著降低HNSCC细胞系中的葡萄糖摄取、乳酸生成和ATP生成。PFK15抑制细胞增殖，阻止细胞周期进程并诱导细胞凋亡。PFK15处理后，HNSCC细胞的侵袭伪足明显减少，从而损害细胞迁移和细胞外基质降解能力。异种移植小鼠模型的体内数据证明，给予PFK15可抑制肿瘤生长。转移小鼠模型的结果显示，给予PFK15可减轻HNSCC的肺转移并延长小鼠的预期寿命。
通过PFK15对PFKFB3进行药理抑制可抑制HNSCC的肿瘤生长并减轻转移，为癌症治疗提供了一种有前景的策略。
