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p53-Mediated Oxidative Stress Enhances Indirubin-3′-Monoxime-Induced Apoptosis in HCT116 Colon Cancer Cells by Upregulating Death Receptor 5 and TNF-Related Apoptosis-Inducing Ligand Expression

1
Department of Marine Life Science, Jeju National University, Jeju 63243, Korea
2
Department of Food Technology, Faculty of Technology, Rajarata University of Sri Lanka, Mihintale 50300, Sri Lanka
3
Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan 47227, Korea
4
Department of Molecular Biology, College of Natural Sciences and Human Ecology, Dongeui University, Busan 47340, Korea
5
Forest Biomaterials Research Center, National Institute of Forest Science, Jinju 52817, Korea
*
Authors to whom correspondence should be addressed.
These authors equally contributed to this work.
Antioxidants 2019, 8(10), 423; https://doi.org/10.3390/antiox8100423
Received: 15 August 2019 / Revised: 19 September 2019 / Accepted: 20 September 2019 / Published: 22 September 2019
(This article belongs to the Section Aberrant Oxidation of Biomolecules)
Indirubin-3′-monoxime (I3M) exhibits anti-proliferative activity in various cancer cells; however, its anti-cancer mechanism remains incompletely elucidated. This study revealed that I3M promotes the expression of death receptor 5 (DR5) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in HCT116 p53+/+ cells, resulting in caspase-mediated apoptosis. However, this study demonstrated that HCT116 p53−/− cells were insensitive to I3M-mediated apoptosis, indicating that I3M-induced apoptosis depends on the p53 status of HCT116 cells. Additionally, in HCT116 p53-/- cells, I3M significantly increased Ras expression, while in HCT116 p53+/+ cells, it reduced Ras expression. Furthermore, I3M remarkably increased the production of reactive oxygen species (ROS), which were reduced in transient p53 knockdown, indicating that I3M-mediated apoptosis was promoted by p53-mediated ROS production. Our results also showed that I3M enhanced transcription factor C/EBP homologous protein (CHOP) expression, resulted in endoplasmic reticulum (ER) stress-mediated DR5 expression, which was upregulated by ROS production in HCT116 p53+/+ cells. Moreover, co-treatment with I3M and TRAIL enhanced DR5 expression, thereby triggering TRAIL-induced apoptosis of HCT116 p53+/+ cells, which was interfered by a DR5-specific blocking chimeric antibody. In summary, I3M potently enhances TRAIL-induced apoptosis by upregulating DR5 expression via p53-mediated ROS production in HCT116 p53+/+ cells. However, HCT116 p53−/− cells were less sensitive to I3M-mediated apoptosis, suggesting that I3M could be a promising anti-cancer candidate against TRAIL-resistant p53+/+ cancer cells. Additionally, this study also revealed that I3M sensitizes colorectal cancer cells such as HT29 and SW480 to TRAIL-mediated apoptosis. View Full-Text
Keywords: indirubin-3′-monoxime; p53; death receptor 5; TNF-related apoptosis-inducing ligand; transcription factor C/EBP homologous protein indirubin-3′-monoxime; p53; death receptor 5; TNF-related apoptosis-inducing ligand; transcription factor C/EBP homologous protein
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Dilshara, M.G.; Molagoda, I.M.N.; Jayasooriya, R.G.P.T.; Choi, Y.H.; Park, C.; Lee, K.T.; Lee, S.; Kim, G.-Y. p53-Mediated Oxidative Stress Enhances Indirubin-3′-Monoxime-Induced Apoptosis in HCT116 Colon Cancer Cells by Upregulating Death Receptor 5 and TNF-Related Apoptosis-Inducing Ligand Expression. Antioxidants 2019, 8, 423.

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