Wang Ke, Fan Hua, Chen Qingsen, Ma Guojian, Zhu Ming, Zhang Xiaomei, Zhang Yuanying, Yu Jun
aJiangsu Institute of Cancer Research bJiangsu Research Institute of Geriatrics, Nanjing, China.
Anticancer Drugs. 2015 Jan;26(1):15-24. doi: 10.1097/CAD.0000000000000132.
Curcumin, the major pigment of the dietary spice turmeric, has the potential for chemoprevention by promotion of apoptosis. Here, we investigated the molecular mechanisms of curcumin in glycolytic inhibition and apoptotic induction in human colorectal cancer HCT116 and HT29 cells. On the one hand, curcumin downregulated the expression and activity of hexokinase II (HKII) in HCT116 and HT29 cells in a concentration-dependent manner, but had little effect on the other key glycolytic enzymes (PFK, PGM, and LDH). On the other, curcumin induced dissociation of HKII from the mitochondria, resulting in mitochondrial-mediated apoptosis. Furthermore, the phosphorylation of mitochondrial HKII through AKT was responsible for the curcumin-induced dissociation of HKII, which was different from the mechanism of HKII inhibitor 3-BrPA. These results have important implications for the metabolism reprogramming effect and the susceptibility to curcumin-induced mitochondrial cytotoxicity through the regulation of HKII, and provide a molecular basis for the development of naturally compounds as novel anticancer agents for colorectal carcinoma.
姜黄素是膳食香料姜黄中的主要色素，具有通过促进细胞凋亡实现化学预防的潜力。在此，我们研究了姜黄素在人结肠癌细胞HCT116和HT29细胞中抑制糖酵解和诱导凋亡的分子机制。一方面，姜黄素以浓度依赖的方式下调HCT116和HT29细胞中己糖激酶II（HKII）的表达和活性，但对其他关键糖酵解酶（PFK、PGM和LDH）影响很小。另一方面，姜黄素诱导HKII从线粒体解离，导致线粒体介导的细胞凋亡。此外，通过AKT对线粒体HKII的磷酸化导致了姜黄素诱导的HKII解离，这与HKII抑制剂3-BrPA的作用机制不同。这些结果对于通过调节HKII产生的代谢重编程效应以及对姜黄素诱导的线粒体细胞毒性的敏感性具有重要意义，并为开发天然化合物作为结直肠癌新型抗癌药物提供了分子基础。
