Death receptor 5-mediated TNFR family signaling pathways modulate γ-humulene-induced apoptosis in human colorectal cancer HT29 cells
- Yu-Hsuan Lan
- Yang-Chang Wu
- Kai-Wei Wu
- Jing-Gung Chung
- Chi-Cheng Lu
- Yuan-Liang Chen
- Tian-Shung Wu
- Jai-Sing Yang
Affiliations: School of Pharmacy, China Medical University, Taichung 404, Taiwan, R.O.C., School of Pharmacy, China Medical University, No 91, Hsueh-Shih Road, Taichung 40402, Taiwan, R.O.C., Department of Pharmacology, China Medical University, No 91, Hsueh-Shih Road, Taichung 40402, Taiwan. R.O.C.
- Published online on: December 8, 2010 https://doi.org/10.3892/or.2010.1087
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A component from Emilia sonchifolia (L.) DC, γ-humulene, was investigated. Significantly decreased cell viability of human colorectal cancer HT29 cells in a dose-dependent manner with IC50 53.67±2.99 μM for 24-h treatment was found. γ-Humulene induced apoptotic cell death and apoptosis was confirmed by morphological assessment. The staining with propidium iodide (PI) and flow cytometric analysis also showed that γ-humulene significantly promoted the sub-G1 phase (an apoptotic population) in HT29 cells. Colorimetric assays indicated that pretreatment with a specific inhibitor of caspase-8 (Z-IETD-FMK) significantly reduced activities of caspase-8 and caspase-3 in examined HT29 cells. γ-Humulene stimulated the death receptor 5 (DR5), DR4, Fas-associated protein with death domain (FADD), the cleavage of caspase-8 and cleavage caspase-3, but reduced the protein levels of cellular Fas-associated death-domain-like IL-1ß-converting enzyme inhibitory protein (c-FLIP) by Western blot analysis. Consequently, γ-humulene-triggered cell death was significantly attenuated by DR5 siRNA and the caspase-8 inhibitor. Based on our results, we suggest that γ-humulene induced apoptotic cell death in HT29 cells through a DR5-mediated caspase-8 and -3-dependent signaling pathway. Therefore, this agent might be useful for developing new therapeutic regimens for treatment of colorectal cancer in the future.