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3,3′-Diindolylmethane Suppresses the Growth of Hepatocellular Carcinoma by Regulating Its Invasion, Migration, and ER Stress-Mediated Mitochondrial Apoptosis

1
Laboratory of Liver Regeneration, Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju 54907, Korea
2
Alka Hospital Private Limited, Jwalakhel, Kathmandu 446010, Nepal
3
Department of Surgery, Jeonbuk National University Hospital, Jeonju 54907, Korea
4
Department of Pharmacology and New Drug Development Research Institute, Jeonbuk National University Hospital, Jeonju 54907, Korea
*
Author to whom correspondence should be addressed.
Academic Editors: Stefania Meschini and Maria Condello
Cells 2021, 10(5), 1178; https://doi.org/10.3390/cells10051178
Received: 26 March 2021 / Revised: 30 April 2021 / Accepted: 5 May 2021 / Published: 12 May 2021
(This article belongs to the Special Issue Cancer Therapy Based on Oxidative Stress Modulation)
Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death worldwide with limited treatment options. Biomarker-based active phenolic flavonoids isolated from medicinal plants might shed some light on potential therapeutics for treating HCC. 3,3′-diindolylmethane (DIM) is a unique biologically active dimer of indole-3-carbinol (I3C), a phytochemical compound derived from Brassica species of cruciferous vegetables—such as broccoli, kale, cabbage, and cauliflower. It has anti-cancer effects on various cancers such as breast cancer, prostate cancer, endometrial cancer, and colon cancer. However, the molecular mechanism of DIM involved in reducing cancer risk and/or enhancing therapy remains unknown. The aim of the present study was to evaluate anti-cancer and therapeutic effects of DIM in human hepatoma cell lines Hep3B and HuhCell proliferation was measured with MTT and trypan blue colony formation assays. Migration, invasion, and apoptosis were measured with Transwell assays and flow cytometry analyses. Reactive oxygen species (ROS) intensity and the loss in mitochondrial membrane potential of Hep3B and Huh7 cells were determined using dihydroethidium (DHE) staining and tetramethylrhodamine ethyl ester dye. Results showed that DIM significantly suppressed HCC cell growth, proliferation, migration, and invasion in a concentration-dependent manner. Furthermore, DIM treatment activated caspase-dependent apoptotic pathway and suppressed epithelial–mesenchymal transition (EMT) via ER stress and unfolded protein response (UPR). Taken together, our results suggest that DIM is a potential anticancer drug for HCC therapy by targeting ER-stress/UPR. View Full-Text
Keywords: ER stress; unfolded protein response; hepatocellular carcinoma; apoptosis; EMT; DIM ER stress; unfolded protein response; hepatocellular carcinoma; apoptosis; EMT; DIM
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MDPI and ACS Style

Munakarmi, S.; Shrestha, J.; Shin, H.-B.; Lee, G.-H.; Jeong, Y.-J. 3,3′-Diindolylmethane Suppresses the Growth of Hepatocellular Carcinoma by Regulating Its Invasion, Migration, and ER Stress-Mediated Mitochondrial Apoptosis. Cells 2021, 10, 1178. https://doi.org/10.3390/cells10051178

AMA Style

Munakarmi S, Shrestha J, Shin H-B, Lee G-H, Jeong Y-J. 3,3′-Diindolylmethane Suppresses the Growth of Hepatocellular Carcinoma by Regulating Its Invasion, Migration, and ER Stress-Mediated Mitochondrial Apoptosis. Cells. 2021; 10(5):1178. https://doi.org/10.3390/cells10051178

Chicago/Turabian Style

Munakarmi, Suvesh, Juna Shrestha, Hyun-Beak Shin, Geum-Hwa Lee, and Yeon-Jun Jeong. 2021. "3,3′-Diindolylmethane Suppresses the Growth of Hepatocellular Carcinoma by Regulating Its Invasion, Migration, and ER Stress-Mediated Mitochondrial Apoptosis" Cells 10, no. 5: 1178. https://doi.org/10.3390/cells10051178

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