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An anthraquinone derivative, emodin sensitizes hepatocellular carcinoma cells to TRAIL induced apoptosis through the induction of death receptors and downregulation of cell survival proteins |
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| Authors: | Aruljothi Subramaniam Ser Yue Loo Peramaiyan Rajendran Kanjoormana A Manu Ekambaram Perumal Feng Li Muthu K Shanmugam Kodappully Sivaraman Siveen Joo-In Park Kwang Seok Ahn Kam M Hui Alan P Kumar Gautam Sethi |
| Institution: | 1. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore 2. Molecular Toxicology Lab, Department of Biotechnology, Bharathiar University, Coimbatore, 641046, Tamil Nadu, India 3. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore 4. Centre for Translational Medicine, Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, #11-01 M, Singapore, 117599, Singapore 5. Department of Biochemistry, Dong-A University College of Medicine and Medical Research Center for Cancer Molecular Therapy, Dong-A University, Busan, Republic of Korea 6. College of Oriental Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea 7. Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore, 169610, Singapore 10. Cancer Science Institute of Singapore, National University of Singapore, 28 Medical Drive, Singapore, 117456, Singapore 8. Faculty of Health Sciences, School of Biomedical Sciences, Curtin University, Bentley, WA, Australia 9. Department of Biological Sciences, University of North Texas, Denton, TX, USA |
| Abstract: | Recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is currently under clinical trials for cancer, however many tumor cells, including hepatocellular carcinoma (HCC) develop resistance to TRAIL-induced apoptosis. Hence, novel agents that can alleviate TRAIL-induced resistance are urgently needed. In the present report, we investigated the potential of emodin to enhance apoptosis induced by TRAIL in HCC cells. As observed by MTT cytotoxicity assay and the externalization of the membrane phospholipid phosphatidylserine, we found that emodin can significantly potentiate TRAIL-induced apoptosis in HCC cells. When investigated for the mechanism(s), we observed that emodin can downregulate the expression of various cell survival proteins, and induce the cell surface expression of both TRAIL receptors, death receptors (DR) 4 as well as 5. In addition, emodin increased the expression of C/EBP homologous protein (CHOP) in a time-dependent manner. Knockdown of CHOP by siRNA decreased the induction of emodin-induced DR5 expression and apoptosis. Emodin-induced induction of DR5 was mediated through the generation of reactive oxygen species (ROS), as N-acetylcysteine blocked the induction of DR5 and the induction of apoptosis. Also, the knockdown of X-linked inhibitor of apoptosis protein by siRNA significantly reduced the sensitization effect of emodin on TRAIL-induced apoptosis. Overall, our experimental results clearly indicate that emodin can indeed potentiate TRAIL-induced apoptosis through the downregulation of antiapoptotic proteins, increased expression of apoptotic proteins, and ROS mediated upregulation of DR in HCC cells. |
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