Shan Shuhua, Shi Jiangying, Yang Peng, Jia Bin, Wu Haili, Zhang Xiaoli, Li Zhuoyu
Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Institute of Biotechnology, Shanxi University , Taiyuan 030006, China.
Department of Biology, Taiyuan Normal University , Taiyuan 030619, China.
J Agric Food Chem. 2017 Sep 20;65(37):8136-8144. doi: 10.1021/acs.jafc.7b02757. Epub 2017 Sep 11.
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 IC values of AP against HCT116, HT29, and DLD1 cells were 27.9 ± 2.45, 48.2 ± 3.01 and 89.5 ± 4.89 μM, 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 β-catenin/c-Myc/PTBP1 signal pathway. Hence, PKM2 represents a novel potential target of AP against colon cancer.
芹菜素（AP）作为一种抗癌剂，已被广泛研究。然而，芹菜素在肿瘤代谢方面的分子靶点尚不清楚。在此，我们发现AP可通过抑制肿瘤特异性丙酮酸激酶M2（PKM2）的活性和表达来阻断细胞糖酵解，并进一步显著诱导抗结肠癌效应。AP对HCT116、HT29和DLD1细胞的IC值分别为27.9±2.45、48.2±3.01和89.5±4.89μM。荧光光谱和固相AP提取试验证明，AP可直接与PKM2结合，并在体外和HCT116细胞中显著抑制PKM2活性。有趣的是，在存在d-果糖-1,6-二磷酸（FBP）的情况下，AP对PKM2的抑制作用并未逆转，这表明AP是PKM2的一种新型变构抑制剂。RT-PCR和蛋白质印迹分析表明，AP可通过阻断β-连环蛋白/c-Myc/PTBP1信号通路，确保HCT116细胞中PKM2/PKM1的比例较低。因此，PKM2是AP抗结肠癌的一个新的潜在靶点。
