Silibinin induces apoptosis of HT29 colon carcinoma cells through early growth response-1 (EGR-1)-mediated non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1) up-regulation.

Abstract

Silibinin, an effective anti-cancer and chemopreventive agent, has been shown to exert multiple effects on cancer cells, including inhibition of both cell proliferation and migration. However, the molecular mechanisms responsible for these effects are not fully understood. We observed that silibinin significantly induced the expression of the non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1) in both p53 wild-type and p53-null cancer cell lines, suggesting that silibinin-induced NAG-1 up-regulation is p53-independent manner. Silibinin up-regulates early growth response-1 (EGR-1) expression. The ectopic expression of EGR-1 significantly increased NAG-1 promoter activity and NAG-1 protein expression in a dose-dependent manner. Furthermore, down-regulation of EGR-1 expression using siRNA markedly reduced silibinin-mediated NAG-1 expression, suggesting that the expression of EGR-1 is critical for silibinin-induced NAG-1 expression. We also observed that reactive oxygen species (ROS) are generated by silibinin; however, ROS did not affect silibinin-induced NAG-1 expression and apoptosis. In addition, we demonstrated that the mitogen-activated protein kinase (MAP kinase) signal transduction pathway is involved in silibinin-induced NAG-1 expression. Inhibitors of p38 MAP kinase (SB203580) attenuated silibinin-induced NAG-1 expression. Furthermore, we found that siRNA-mediated knockdown of NAG-1 attenuated silibinin-induced apoptosis. Collectively, the results of this study demonstrate for the first time that up-regulation of NAG-1 contributes to silibinin-induced apoptosis in cancer cells.

• Authors: Seon Min Woo, Kyoung-Jin Min, Shin Kim, Jong-Wook Park, Dong Eun Kim, Kyung-Soo Chun, Young Ho Kim, Tae-Jin Lee, Sang Hyun Kim, Yung Hyun Choi, Jong-Soo Chang, Taeg Kyu Kwon
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 211 Pg. 36-43 (Mar 25 2014) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 24440808 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Antioxidants
• Early Growth Response Protein 1
• GDF15 protein, human
• Growth Differentiation Factor 15
• Silymarin
• Silybin

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Antioxidants (pharmacology)
• Apoptosis (drug effects)
• Caco-2 Cells
• Cell Line
• Cell Line, Tumor
• Early Growth Response Protein 1 (metabolism)
• Growth Differentiation Factor 15 (genetics, metabolism)
• HCT116 Cells
• HT29 Cells
• Humans
• Mice
• Silybin
• Silymarin (pharmacology)
• Up-Regulation (drug effects)