Rhein induces apoptosis through induction of endoplasmic reticulum stress and Ca2+-dependent mitochondrial death pathway in human nasopharyngeal carcinoma cells.
Apoptosis is a physiological mechanism for eliminating malignant cells, including cancer cells, without eliciting damage to normal cells or surrounding tissues. Here, we report that rhein (4,5-dihydroxyanthraquinone-2-carboxylic acid), a major constituent in the rhizome of rhubarb, induced apoptosis of human nasopharyngeal carcinoma (NPC) cells. Rhein induced apoptosis in NPC cells as demonstrated by increased nuclear condensation and DNA fragmentation. Moreover, for the first time in NPC cells it was demonstrated that the pathway involved in rhein-induced apoptosis is caspase-dependent, presumably through the endoplasmic reticulum (ER) stress pathway, as shown by an increase in the levels of glucose-regulated protein 78 (GRP 78), PKR-like ER kinase (PERK), activating transcription factor 6 (A TF6) and CCAA TIenhancer-binding protein homologous protein (CHOP) as well as the activation of caspase-3, -8, -9 and -12. This increased susceptibility to ER stress-induced apoptosis may be due to an increased accumulation of reactive oxygen species (ROS). Rapid accumulation of calcium (Ca2+) and a decrease in the mitochondrial membrane potential (MMP) were also observed. Cytochrome c and apoptosis-inducing factor (AIF) were released upon treatment with rhein. Taken together, these results suggest that ER stress and Ca2+-dependent mitochondrial death pathway may be involved in rhein-induced apoptosis in NPC cells.
Lin
Meng-Liang
ML
School of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan, ROC.
Chen
Shih-Shun
SS
Lu
Yao-Cheng
YC
Liang
Rui-Yue
RY
Ho
Yung-Tsuan
YT
Yang
Chiou-Ying
CY
Chung
Jing-Gung
JG
D000880:Anthraquinones / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051742:Transcription Factor CHOP / Q000096:biosynthesis
D000880:Anthraquinones; C497249:DDIT3 protein, human; D051742:Transcription Factor CHOP; D002118:Calcium; C020491:rhein