Kaempferol inhibits cell proliferation and glycolysis in esophagus squamous cell carcinoma via targeting EGFR signaling pathway
Kaempferol inhibits cell proliferation and glycolysis in esophagus squamous cell carcinoma via targeting EGFR signaling pathway
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山奈酚通过靶向EGFR信号通路抑制食管鳞癌细胞增殖和糖酵解
DOI：
10.1007/s13277-016-4912-6
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发表时间：
2016-08-01
期刊：
影响因子：
--
通讯作者：
Fang, Wentao
中科院分区：
文献类型：
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作者：
Yao, Shihua;Wang, Xiaowei;Fang, Wentao
山奈酚的抗肿瘤活性已被研究，但其在食管鳞状细胞癌中的作用尚不清楚。本文报道山奈酚抗食管鳞状细胞癌的活性及其抗肿瘤机制。细胞增殖和集落形成实验结果表明，山奈酚能显著抑制体外肿瘤细胞增殖和克隆形成。流式细胞术分析显示山奈酚处理后肿瘤细胞G0/G1期阻滞，参与细胞周期调控的蛋白表达发生显著变化。除了对细胞增殖的抑制作用外，我们还发现山奈酚对肿瘤糖酵解有明显的抑制作用。随着己糖激酶-2的下调，肿瘤细胞的葡萄糖摄取和乳酸生成显著下降。机制研究表明山奈酚对表皮生长因子受体（EGFR）活性有直接影响，在抑制EGFR的同时，其下游信号通路也明显受到抑制。进一步研究发现，肿瘤细胞中外源性过表达EGFR显著减弱山奈酚诱导的糖酵解抑制，这表明EGFR在山奈酚介导的糖酵解抑制中也发挥了重要作用。最后，在异种移植物模型中验证了山奈酚的抗肿瘤活性，山奈酚在体内明显抑制肿瘤生长。同时，山奈酚处理的肿瘤组织中EGFR活性和己糖激酶-2表达显著降低，证实了这些结果。简而言之，这些研究表明山奈酚或其类似物可能是治疗食管鳞状细胞癌的有效候选药物。
Antitumor activity of kaempferol has been studied in various tumor types, but its potency in esophagus squamous cell carcinoma is rarely known. Here, we reported the activity of kaempferol against esophagus squamous cell carcinoma as well as its antitumor mechanisms. Results of cell proliferation and colony formation assay showed that kaempferol substantially inhibited tumor cell proliferation and clone formation in vitro. Flow cytometric analysis demonstrated that tumor cells were induced G0/G1 phase arrest after kaempferol treatment, and the expression of protein involved in cell cycle regulation was dramatically changed. Except the potency on cell proliferation, we also discovered that kaempferol had a significant inhibitory effect against tumor glycolysis. With the downregulation of hexokinase-2, glucose uptake and lactate production in tumor cells were dramatically declined. Mechanism studies revealed kaempferol had a direct effect on epidermal growth factor receptor (EGFR) activity, and along with the inhibition of EGFR, its downstream signaling pathways were also markedly suppressed. Further investigations found that exogenous overexpression of EGFR in tumor cells substantially attenuated glycolysis suppression induced by kaempferol, which implied that EGFR also played an important role in kaempferol-mediated glycolysis inhibition. Finally, the antitumor activity of kaempferol was validated in xenograft model and kaempferol prominently restrained tumor growth in vivo. Meanwhile, dramatic decrease of EGFR activity and hexokinase-2 expression were observed in kaempferol-treated tumor tissue, which confirmed these findings in vitro. Briefly, these studies suggested that kaempferol, or its analogues, may serve as effective candidates for esophagus squamous cell carcinoma management.