Esculetin induces apoptosis of SMMC-7721 cells through IGF-1/PI3K/Akt-mediated mitochondrial pathways

Esculetin (6,7-dihydroxycoumarin) is a coumarin derivative extracted from natural plants and has been reported to have anti-cancer activity. However, the mechanism by which esculetin prevents human hepatic cancer cell growth is still largely unknown. In this study, we investigated the effect of esculetin on human hepatocellular carcinoma (HCC) SMMC-7721 cells and explored the cell signal mechanism. Our data indicated that esculetin induced apoptosis in SMMC-7721 cells, which were supported by DAPI staining and Annexin V/PI staining. Meanwhile, esculetin increased the activities of caspase-3 and caspase-9, promoted bax expression, decreased bcl-2 expression, and triggered collapse of mitochondrial membrane potential, cytochrome c release from mitochondria. In addition, the inactivation of IGF-1, PI3K and Akt was observed after esculetin administration. Furthermore, pretreatment with IGR-1 before esculetin administration abrogated the pro-apoptotic effects of esculetin. While PI3K inhibitor increased the pro-apoptotic effects of esculetin. These results indicated that esculetin induced the apoptosis of SMMC-7721 cells through IGF-1/PI3K/Akt-regulated mitochondrial dysfunction.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author