Matrine Reverses the Warburg Effect and Suppresses Colon Cancer Cell Growth via Negatively Regulating HIF-1α
Matrine Reverses the Warburg Effect and Suppresses Colon Cancer Cell Growth via Negatively Regulating HIF-1α
复制标题
苦参碱通过负调节 HIF-1α 逆转 Warburg 效应并抑制结肠癌细胞生长
DOI：
10.3389/fphar.2019.01437
复制
发表时间：
2019-11-28
影响因子：
5.6
通讯作者：
Zhan, Yan-yan
中科院分区：
文献类型：
--
作者：
Hong, Xiaoting;Zhong, Linhai;Zhan, Yan-yan
瓦尔堡效应是癌症代谢的一个独特特征，它是一个有吸引力的治疗靶点，可以瞄准肿瘤细胞，同时保留正常组织。苦参碱是从传统中药苦参（Sophora flavescens Ait）的草本根中提取的生物碱。苦参碱已被报道对癌细胞具有选择性细胞毒性，但其机制尚不清楚。在此，我们报道了苦参碱能够逆转瓦尔堡效应（抑制葡萄糖摄取和乳酸产生），并在体外和体内抑制人结肠癌细胞的生长。从机制上讲，我们发现苦参碱显著降低了HIF-1 α的信使RNA（mRNA）和蛋白质表达，HIF-1 α是重编程癌症代谢向瓦尔堡效应的关键转录因子。因此，GLUT 1，HK 2和LDHA的表达水平，HIF-1 α在调节葡萄糖代谢的下游目标，显着抑制苦参碱。此外，当结肠癌细胞中HIF-1 α被敲低或外源性过表达时，苦参碱的这种抑制作用显著减弱。总之，我们的研究结果表明，苦参碱抑制结肠癌细胞生长通过抑制HIF-1 α的表达和其下游调节的瓦尔堡效应。苦参碱可进一步开发为靶向HIF-1 α介导的瓦尔堡效应的抗肿瘤剂，用于结肠癌治疗。
The Warburg effect is a peculiar feature of cancer's metabolism, which is an attractive therapeutic target that could aim tumor cells while sparing normal tissue. Matrine is an alkaloid extracted from the herb root of a traditional Chinese medicine, Sophora flavescens Ait. Matrine has been reported to have selective cytotoxicity toward cancer cells but with elusive mechanisms. Here, we reported that matrine was able to reverse the Warburg effect (inhibiting glucose uptake and lactate production) and suppress the growth of human colon cancer cells in vitro and in vivo. Mechanistically, we revealed that matrine significantly decreased the messenger RNA (mRNA) and protein expression of HIF-1 alpha, a critical transcription factor in reprogramming cancer metabolism toward the Warburg effect. As a result, the expression levels of GLUT1, HK2, and LDHA, the downstream targets of HIF-1 alpha in regulating glucose metabolism, were dramatically inhibited by matrine. Moreover, this inhibitory effect of matrine was significantly attenuated when HIF-1 alpha was knocked down or exogenous overexpressed in colon cancer cells. Together, our results revealed that matrine inhibits colon cancer cell growth via suppression of HIF-1 alpha expression and its downstream regulation of Warburg effect. Matrine could be further developed as an antitumor agent targeting the HIF-1 alpha-mediated Warburg effect for colon cancer treatment.