Department of Nutrition and Health Sciences, Chang Jung Christian University, Tainan 71101, Taiwan.
Food Funct. 2010 Dec;1(3):301-7. doi: 10.1039/c0fo00134a. Epub 2010 Oct 27.
Garcinol, derived from Garcinia indica and other related species, has been found to modulate several cell 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.
姜黄素，来源于藤黄属植物和其他相关物种，已被发现能调节多种细胞信号通路，这些信号通路参与细胞凋亡和癌症的发生发展。生长停滞和 DNA 损伤诱导基因 153（GADD153）是 CCAAT/增强子结合蛋白（C/EBP）家族转录因子的一员；在正常情况下，其表达水平较低，但在生长停滞、DNA 损伤和内质网（ER）应激时强烈诱导表达。本研究探讨了姜黄素对 Hep3B 细胞（一种缺乏功能性 p53 的人肝癌细胞系）的影响，旨在阐明肝癌中 p53 非依赖性细胞凋亡的分子机制。总的来说，姜黄素不仅激活了死亡受体和线粒体凋亡途径，还激活了 ER 应激调节剂 GADD153。姜黄素处理导致活性氧（ROS）积累、GADD153 表达增加和线粒体膜电位降低。Bax/Bcl-2 比值增加导致细胞凋亡增强。Caspase-8 和 tBid（截短的 Bid）的表达也呈时间依赖性增加。Caspase-3 和 Caspase-9 的酶活性分别增加了约 13 倍和 7.8 倍。此外，多聚（ADP-核糖）聚合酶（PARP）和 DNA 片段化因子-45（DFF-45）的蛋白水解裂解呈剂量和时间依赖性增加。我们的数据表明，姜黄素在 p53 非依赖性癌症凋亡中有很好的治疗应用前景。
