Inhibition of glycolytic activator PFKFB3 suppresses tumor growth and induces tumor vessel normalization in hepatocellular carcinoma
Inhibition of glycolytic activator PFKFB3 suppresses tumor growth and induces tumor vessel normalization in hepatocellular carcinoma
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DOI：
10.1016/j.canlet.2020.12.011
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发表时间：
2021-03-01
期刊：
影响因子：
9.7
通讯作者：
Eguchi, Hidetoshi
中科院分区：
文献类型：
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作者：
Matsumoto, Kenichi;Noda, Takehiro;Eguchi, Hidetoshi
糖酵解已成为治疗恶性肿瘤的新靶点。抑制糖酵解激活因子PFKFB3，修复肿瘤内皮细胞功能，使肿瘤微环境正常化。我们旨在探讨PFKFB3在HCC中的意义，以及PFKFB3抑制剂PFK15在HCC肿瘤细胞和肿瘤内皮细胞中的作用。肝癌组织中PFKFB3和CD31的双重免疫荧光染色显示，肿瘤细胞和肿瘤内皮细胞中PFKFB3的高表达与预后不良显著相关。多变量分析发现PFKFB3表达是一个独立的预后因素。PFK15在体外抑制肝癌细胞系和肿瘤内皮细胞的增殖。在具有肿瘤内皮细胞的肝癌细胞系皮下肿瘤模型中，PFK15抑制肿瘤生长并诱导细胞凋亡。此外，PFK15治疗诱导肿瘤血管正常化，降低血管直径并伴有周细胞附着，改善血管灌注。肿瘤细胞和肿瘤内皮细胞中PFKFB3的高表达被认为是HCC的一种新的预后标志物。通过PFK15靶向PFKFB3可能是抑制肿瘤生长和诱导肿瘤血管正常化的有希望的策略。
Glycolysis emerges as a new therapeutic target for malignancies. The inhibition of glycolytic activator, PFKFB3, repairs tumor endothelial cell function, and normalizing the tumor microenvironment. We aimed to investigate the significance of PFKFB3 in HCC, and the effects of the PFKFB3 inhibitor, PFK15, in HCC tumor cells and tumor endothelial cells. Double immunofluorescent staining of PFKFB3 and CD31 in HCC tissues revealed that high PFKFB3 expression in both tumor cells and tumor endothelial cells was significantly correlated with poor prognosis. Multivariate analysis identified PFKFB3 expression as an independent prognostic factor. PFK15 suppressed proliferation of HCC cell line and tumor endothelial cells in vitro. In a subcutaneous tumor model of the HCC cell line with tumor endothelial cells, PFK15 suppressed tumor growth and induced apoptosis. Moreover, PFK15 treatment induced tumor vessel normalization, decreasing vessel diameter with pericyte attachment and improving vessel perfusion. High PFKFB3 expression in both tumor cells and tumor endothelial cells was identified as a novel prognostic marker in HCC. Targeting PFKFB3 via PFK15 might be a promising strategy for suppressing tumor growth and inducing tumor vessel normalization.