Blockage of glycolysis by targeting PFKFB3 suppresses tumor growth and metastasis in head and neck squamous cell carcinoma

Abstract

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 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.ConclusionsThe pharmacological inhibition of PFKFB3 via PFK15 suppressed tumor growth and alleviated metastasis in HNSCC, offering a promising strategy for cancer therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0481-1) contains supplementary material, which is available to authorized users.

Lymphotoxin‐α promotes tumor angiogenesis in HNSCC by modulating glycolysis in a PFKFB3‐dependent manner

“…PFK15 treatment significantly reduced the tumor volume (Fig. g ), in accordance with our previous research . Our immunohistochemistry results verified that PFK15 administration significantly reduced the CD31 positive vessels in HNSCC xenografts compared to those in the tumors treated with vehicles (Figs.…”

“…The methods were carried out in accordance with the approved guidelines and regulations. According to previous study, about 1 × 10 7 viable Cal27 cells re‐suspended in 100 μL PBS were subcutaneously injected into 12 mice to establish the HNSCC xenografts. After 2 weeks when subcutaneous tumors were visible, the mice were then randomly divided into two groups, which received either intraperitoneal injection of PFK15 (20 mg/kg; n = 6) or PBS (vehicle, 100 μL; n = 6) three times per week for 2 weeks.…”

PFKFB4 Promotes Breast Cancer Metastasis via Induction of Hyaluronan Production in a p38-Dependent Manner

“…In addition, PFKFB3 plays a role in tumor metastasis in head and neck squamous cell carcinoma and nasopharyngeal carcinoma [36,37]. Previous reports indicate that HA accumulation occurs in numerous tumor types and thereby facilitates the progression and metastasis of carcinomas [38,39].…”

Inhibition of PFKFB3 suppresses osteoclastogenesis and prevents ovariectomy‐induced bone loss

“…29 In recent studies, blockage of PFKFB3 suppressed the growth of various cancer cells, such as head and neck squamous cell carcinoma cells 17 and breast cancer cells. 29 In recent studies, blockage of PFKFB3 suppressed the growth of various cancer cells, such as head and neck squamous cell carcinoma cells 17 and breast cancer cells.…”

“…Li et al 17 showed that pharmacological inhibition of PFKFB3 with its inhibitor PFK15 suppressed the growth of head and neck squamous cell carcinoma by reducing glycolytic flux. Previous studies concerning PFKFB3 mainly focused on its role in cancer.…”