Garcinol inhibits cell growth in hepatocellular carcinoma Hep3B cells through induction of ROS-dependent apoptosis
Garcinol inhibits cell growth in hepatocellular carcinoma Hep3B cells through induction of ROS-dependent apoptosis
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DOI：
10.1039/c0fo00134a
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发表时间：
2010-12-01
期刊：
影响因子：
6.1
通讯作者：
Pan, Min-Hsiung
中科院分区：
文献类型：
--
作者：
Cheng, An-Chin;Tsai, Mei-Ling;Pan, Min-Hsiung
Garcinol 源自 Garcinia indica 和其他相关物种，被发现可以调节与细胞凋亡和癌症发展有关的多种信号传导途径。生长停滞和 DNA 损伤诱导基因 153 (GADD153) 是转录因子 CCAAT/增强子结合蛋白 (C/EBP) 家族的成员；它在正常条件下以低水平表达，但在生长停滞、DNA 损伤和内质网 (ER) 应激时强烈诱导。本研究研究了garcinol对Hep3B细胞（一种缺乏功能性p53的人肝细胞癌细胞系）的影响，目的是阐明肝细胞癌中不依赖于p53的细胞凋亡的分子机制。总体而言，藤黄醇不仅激活死亡受体和线粒体凋亡途径，还激活 ER 应激调节剂 GADD153。 Garcinol 处理导致活性氧 (ROS) 积累、GADD153 表达增加、线粒体膜电位降低。 Bax/Bcl-2 比率的增加导致细胞凋亡增强。 Caspase-8 和 tBid（截短的 Bid）表达也以时间依赖性方式增加。 caspase-3 和 caspase-9 的酶活性分别增加约 13 倍和 7.8 倍。此外，聚（ADP-核糖）聚合酶（PARP）和DNA片段因子45（DFF-45）的蛋白水解裂解以剂量和时间依赖性方式增加。我们的数据表明，garcinol 在癌症的 p53 依赖性细胞凋亡中具有广阔的治疗应用前景。
Garcinol, derived from Garcinia indica and other related species, has been found to modulate several call signalling pathways involved in apoptosis and cancer development. Growth arrest and DNA damage-inducible gene 153 (GADD153) is a member of the CCAAT/enhancer-binding protein (C/EBP) family of transcription factors; it is expressed at low levels under normal conditions but strongly induced upon growth arrest, DNA damage, and endoplasmic reticulum (ER) stress. This study investigated the effect of garcinol on Hep3B cells, a human hepatocellular cancer cell line lacking functional p53, with the goal of elucidating the molecular mechanisms of p53-independent apoptosis in hepatocellular cancer. Overall, garcinol activated not only the death receptor and the mitochondrial apoptosis pathways but also the ER stress modulator GADD153. Garcinol treatment led to the accumulation of reactive oxygen species (ROS), increased GADD153 expression, and reduced mitochondrial membrane potential. An increase in the Bax/Bcl-2 ratio resulted in enhanced apoptosis. Caspase-8 and tBid (truncated Bid) expression also increased in a time-dependent manner. The enzymatic activities of caspase-3 and caspase-9 increased approximately 13-fold and 7.8-fold, respectively. In addition, the proteolytic cleavage of poly-(ADP-ribose)-polymerase (PARP) and DNA fragmentation factor-45 (DFF-45) increased in dose- and time-dependent manners. Our data suggest a promising therapeutic application of garcinol in p53-independent apoptosis in cancers.