Nimbolide induced apoptosis by activating ERK‐mediated inhibition of c‐IAP1 expression in human hepatocellular carcinoma cells |
| |
| Authors: | Kuan‐Chun Hsueh Chia‐Liang Lin Jai‐Nien Tung Shun‐Fa Yang Yi‐Hsien Hsieh |
| |
| Affiliation: | 1. Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan;2. Division of General Surgery, Department of Surgery, Tungs' Taichung MetroHarbour Hospital, Taichung, Taiwan;3. Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan;4. Department of Neurosurgery, Tungs'Taichung MetroHarbor Hospital, Taichung, Taiwan;5. Department of Medical Research, Chung Shan Medical University Hospital, Taichung, TaiwanShun‐Fa Yang and Yi‐Hsien Hsieh contributed equally to this work.;6. Department of Biochemistry, School of Medicine, Chung Shan Medical University, Taichung, Taiwan;7. Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, TaiwanShun‐Fa Yang and Yi‐Hsien Hsieh contributed equally to this work. |
| |
| Abstract: | Nimbolide is one of the major compounds from the leaves and flowers of the neem tree and exhibits antitumor properties on various cancer cells. However, no report has shown that nimbolide induces apoptosis in vitro and in vivo in human hepatocellular carcinoma cells. Our results indicated that it inhibited cell growth in Huh‐7 and PLC/PRF/5 cells. We also found that nimbolide induced cell death through the induction of G2/M phase arrest and mitochondrial dysfunction, accompanied by the increased expression of cleaved caspase‐7, caspase‐9, caspase‐3, caspase‐PARP, and Bax and decreased expression of Mcl‐1 and Bcl‐2. A human apoptosis antibody array analysis demonstrated that inhibition of the apoptosis family proteins (XIAP, c‐IAP1, and c‐IAP2) was one of the major targets of nimbolide. Additionally, nimbolide sustained activation of ERK expression. Moreover, pretreatment with U0126 (MEK inhibitor) markedly abolished nimbolide‐inhibited cell viability, induced cell apoptosis, ERK phosphorylation, cleaved caspase‐9, caspase‐3, cleaved‐PARP activation, and increased c‐IAP1 expression in Huh‐7 cells. An in vivo study showed that nimbolide significantly reduced Huh‐7 tumor growth and weight in a xenograft mouse model. This study indicated the antitumor potential of nimbolide in human hepatocellular carcinoma cells. |
| |
| Keywords: | apoptosis c‐IAP1 human hepatocellular carcinoma cells nimbolide |
|
|
