Matrine induces caspase-independent program cell death in hepatocellular carcinoma through bid-mediated nuclear translocation of apoptosis inducing factorReportar como inadecuado




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Molecular Cancer

, 13:59

First Online: 16 March 2014Received: 11 December 2013Accepted: 10 March 2014DOI: 10.1186-1476-4598-13-59

Cite this article as: Zhou, H., Xu, M., Gao, Y. et al. Mol Cancer 2014 13: 59. doi:10.1186-1476-4598-13-59

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.

KeywordsHepatocellular carcinoma Matrine Caspase-independent PCD Bid AIF AbbreviationsAIFApoptosis inducing factor

MNNGN-methyl-N’-nitro-N-nitrosoguanidine

PCDProgram cell death

ciPCDCaspase-independent PCD

ΔΨmMitochondrial transmembrane potential

ROSReactive oxygen species

HCCHepatocellular carcinoma

HBVHepatitis B virus

HCVHepatitis C virus

z-VAD-fmkCarbobenzoxy-valyl-alanyl-aspartyl-O-methyl-fluoromethylketone

DAPI4’,6-diamidino-2-phenylindole.

Electronic supplementary materialThe online version of this article doi:10.1186-1476-4598-13-59 contains supplementary material, which is available to authorized users.

Huan Zhou, Minying Xu contributed equally to this work.

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Autor: Huan Zhou - Minying Xu - Ya Gao - Zhigang Deng - Hanwei Cao - Wenqing Zhang - Qiao Wang - Bing Zhang - Gang Song - Yanyan

Fuente: https://link.springer.com/







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