An anthraquinone derivative, emodin sensitizes hepatocellular carcinoma cells to TRAIL induced apoptosis through the induction of death receptors and downregulation of cell survival proteins
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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Journal Article |
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Springer
2013
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| Online Access: | http://hdl.handle.net/20.500.11937/35723 |
| _version_ | 1848754572925861888 |
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| author | Subramaniam, Aruljothi Loo, Ser Rajendran, P. Manu, K. Permul, E. Li, F. Shanmugam, M. Siveen, K. Park, J. Ahn, K. Hui, K. Kumar, Alan Prem Sethi, G. |
| author_facet | Subramaniam, Aruljothi Loo, Ser Rajendran, P. Manu, K. Permul, E. Li, F. Shanmugam, M. Siveen, K. Park, J. Ahn, K. Hui, K. Kumar, Alan Prem Sethi, G. |
| author_sort | Subramaniam, Aruljothi |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T08:42:33Z |
| format | Journal Article |
| id | curtin-20.500.11937-35723 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T08:42:33Z |
| publishDate | 2013 |
| publisher | Springer |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-357232018-03-29T09:09:00Z An anthraquinone derivative, emodin sensitizes hepatocellular carcinoma cells to TRAIL induced apoptosis through the induction of death receptors and downregulation of cell survival proteins Subramaniam, Aruljothi Loo, Ser Rajendran, P. Manu, K. Permul, E. Li, F. Shanmugam, M. Siveen, K. Park, J. Ahn, K. Hui, K. Kumar, Alan Prem Sethi, G. TRAIL DR5 DR4 Apoptosis Emodin CHOP HCC 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. 2013 Journal Article http://hdl.handle.net/20.500.11937/35723 10.1007/s10495-013-0851-5 Springer restricted |
| spellingShingle | TRAIL DR5 DR4 Apoptosis Emodin CHOP HCC Subramaniam, Aruljothi Loo, Ser Rajendran, P. Manu, K. Permul, E. Li, F. Shanmugam, M. Siveen, K. Park, J. Ahn, K. Hui, K. Kumar, Alan Prem Sethi, G. An anthraquinone derivative, emodin sensitizes hepatocellular carcinoma cells to TRAIL induced apoptosis through the induction of death receptors and downregulation of cell survival proteins |
| title | An anthraquinone derivative, emodin sensitizes hepatocellular carcinoma cells to TRAIL induced apoptosis through the induction of death receptors and downregulation of cell survival proteins |
| title_full | An anthraquinone derivative, emodin sensitizes hepatocellular carcinoma cells to TRAIL induced apoptosis through the induction of death receptors and downregulation of cell survival proteins |
| title_fullStr | An anthraquinone derivative, emodin sensitizes hepatocellular carcinoma cells to TRAIL induced apoptosis through the induction of death receptors and downregulation of cell survival proteins |
| title_full_unstemmed | An anthraquinone derivative, emodin sensitizes hepatocellular carcinoma cells to TRAIL induced apoptosis through the induction of death receptors and downregulation of cell survival proteins |
| title_short | An anthraquinone derivative, emodin sensitizes hepatocellular carcinoma cells to TRAIL induced apoptosis through the induction of death receptors and downregulation of cell survival proteins |
| title_sort | anthraquinone derivative, emodin sensitizes hepatocellular carcinoma cells to trail induced apoptosis through the induction of death receptors and downregulation of cell survival proteins |
| topic | TRAIL DR5 DR4 Apoptosis Emodin CHOP HCC |
| url | http://hdl.handle.net/20.500.11937/35723 |