Apigenin Restrains Colon Cancer Cell Proliferation via Targeted Blocking of Pyruvate Kinase M2-Dependent Glycolysis
Apigenin Restrains Colon Cancer Cell Proliferation via Targeted Blocking of Pyruvate Kinase M2-Dependent Glycolysis
复制标题
芹菜素通过靶向阻断丙酮酸激酶 M2 依赖性糖酵解来抑制结肠癌细胞增殖
DOI：
10.1021/acs.jafc.7b02757
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发表时间：
2017-09-20
影响因子：
6.1
通讯作者：
Li, Zhuoyu
中科院分区：
文献类型：
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作者：
Shan, Shuhua;Shi, Jiangying;Li, Zhuoyu
芹菜素（apigenin，AP）作为一种抗肿瘤药物已被广泛研究。然而，芹菜素对肿瘤代谢的分子靶点尚不清楚。本研究发现AP可通过抑制肿瘤特异性丙酮酸激酶M2（PKM2）的活性和表达，阻断细胞糖酵解，进而发挥显著的抗结肠癌作用。AP对HCT 116、HT 29和DLD 1细胞的IC 50值分别为27.9 +/-2.45、48.2 +/-3.01和89.5 +/-4.89 μ m。荧光光谱和AP固相萃取实验证明AP可直接与PKM 2结合，并在体外和HCT 116细胞中显著抑制PKM 2活性。有趣的是，在D-果糖-1，6-二磷酸（FBP）存在下，AP对PKM 2的抑制作用没有被逆转，这表明AP是PKM 2的一种新的变构抑制剂。RT-PCR和Western blot结果显示AP通过阻断β-catenin/c-Myc/PTBP1信号通路，使HCT 116细胞PKM2/PKM1比例降低。因此，PKM2代表AP抗结肠癌的新的潜在靶点。
Apigenin (AP), as an anticancer agent, has been widely explored. However, the molecular targets of apigenin on tumor metabolism are unclear. Herein, we found that AP could block cellular glycolysis through restraining the tumor -specific pyruvate kinase M2 (PKM2) activity and expression and further significantly induce anti -colon cancer effects. The IC50 values of AP against HCT116, HT29, and DLD1 cells were 27.9 +/- 2.45, 48.2 +/- 3.01 and 89.5 +/- 4.89 mu m,respectively. Fluorescence spectra and solid-phase AP extraction assays proved that AP could directly bind to PKM2 and markedly inhibit PKM2 activity in vitro and in HCT116 cells. Interestingly, in the presence of D-fructose-1,6-diphosphate (FBP), the inhibitory effect of AP on PKM2 was not reversed, which suggests that AP is a new allosteric inhibitor of PKM2. RT-PCR and Western blot assays showed that AP could ensure a low PKM2/PKM1 ratio in HCT116 cells via blocking the,beta-catenin/c-Myc/PTBP1 signal pathway. Hence, PKM2 represents a novel potential target of AP against colon cancer.