法尼酰转移酶
法尼酰转移酶抑制剂
焦磷酸法尼酯
对接(动物)
酶
生物化学
作用机理
体外
癌细胞
化学
法尼基二磷酸法尼基转移酶
体内
激酶
转移酶
预酸化
生物
癌症
ATP合酶
医学
护理部
生物技术
遗传学
作者
Ching–Liang Ho,Jui-Ling Wang,Cheng-Chung Lee,H. Cheng,Wu-Che Wen,Howard Cheng,Miles Chih-Ming Chen
标识
DOI:10.1016/j.biopha.2014.09.008
摘要
Antroquinonol is the smallest anticancer molecule isolated from Antrodia camphorata thus far. The ubiquinone-like structure of Antroquinonol exhibits a broad spectrum of activity against malignancies in vivo and in vitro. However, the mechanism of action of Antroquinonol remains unclear. Here, we provide evidence that Antroquinonol plays a role in the inhibition of Ras and Ras-related small GTP-binding protein functions through the inhibition of protein isoprenyl transferase activity in cancer cells. Using cell line-based assays, we found that the inactive forms of Ras and Rho proteins were significantly elevated after treatment with Antroquinonol. We also demonstrated that Antroquinonol binds directly to farnesyltransferase and geranylgeranyltransferase-I, which are key enzymes involved in activation of Ras-related proteins, and inhibits enzymes activities in vitro. Furthermore, a molecular docking analysis illustrated that the isoprenoid moiety of Antroquinonol binds along the hydrophobic cavity of farnesyltransferase similar to its natural substrate, farnesyl pyrophosphate. In contrast, the ring structure of Antroquinonol lies adjacent to the Ras-CAAX motif-binding site on farnesyltransferase. The molecular docking study also showed a reasonable correlation with the IC50 values of Antroquinonol analogues. We also found that the levels of LC3B-II and the autophagosome-associated LC3 form were also significantly increased in H838 after Antroquinonol administration. In conclusion, Antroquinonol inhibited Ras and Ras-related GTP-binding protein activation through inhibition of protein isoprenyl transferase activity, leading to activation of autophagy and associated mode of cell death in cancer cells.
科研通智能强力驱动
Strongly Powered by AbleSci AI