title: Matrine induces caspase-independent program cell death in hepatocellular carcinoma through bid-mediated nuclear translocation of apoptosis inducing factor.
abstract: Matrine, a clinical drug in China, has been used to treat viral hepatitis, cardiac arrhythmia and skin inflammations. Matrine also exhibits chemotherapeutic potential through its ability to trigger cancer cell death. However, the mechanisms involved are still largely unknown. The objective of this study was to investigate the major determinant for the cell death induced by matrine in human hepatocellular carcinoma. We use human hepatocellular carcinoma cell line HepG2 and human hepatocellular carcinoma xenograft in nude mice as models to study the action of matrine in hepatocellular cancers. We found that caspase-dependent and -independent Program Cell Death (PCD) occurred in matrine-treated HepG2 cells, accompanied by the decreasing of mitochondrial transmembrane potential and the increasing ROS production. Further studies showed that AIF released from the mitochondria to the nucleus, and silencing of AIF reduced the caspase-independent PCD induced by matrine. What's more, AIF nuclear translocation, and the subsequent cell death as well, was prevented by Bid inhibitor BI-6C9, Bid-targeted siRNA and ROS scavenger Tiron. In the in vivo study, matrine significantly attenuated tumor growth with AIF release from mitochondria into nucleus in nude mice. These data imply that matrine potently induce caspase-independent PCD in HepG2 cells through Bid-mediated AIF translocation.
authors.forename: Huan
authors.initials: H
authors.lastname: Zhou
authors.forename: Minying
authors.initials: M
authors.lastname: Xu
authors.forename: Ya
authors.initials: Y
authors.lastname: Gao
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Deng
authors.forename: Hanwei
authors.initials: H
authors.lastname: Cao
authors.forename: Wenqing
authors.initials: W
authors.lastname: Zhang
authors.forename: Qiao
authors.initials: Q
authors.lastname: Wang
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Cancer Research Center, Xiamen University Medical college, Xiamen 361102, China. gangsongsd@xmu.edu.cn.
authors.forename: Gang
authors.initials: G
authors.lastname: Song
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zhan
authors.forename: Tianhui
authors.initials: T
authors.lastname: Hu
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D056945:Hep G2 Cells; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011807:Quinolizines / Q000494:pharmacology*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000093842:Matrines
chemical_list: C494829:AIFM1 protein, human; D000470:Alkaloids; D000970:Antineoplastic Agents; D051033:Apoptosis Inducing Factor; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D011807:Quinolizines; D000093842:Matrines