Death receptor 5-mediated TNFR family signaling pathways modulate γ-humulene-induced apoptosis in human colorectal cancer HT29 cells.

Abstract

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.

• Authors: Yu-Hsuan Lan, Yang-Chang Wu, Kai-Wei Wu, Jing-Gung Chung, Chi-Cheng Lu, Yuan-Liang Chen, Tian-Shung Wu, Jai-Sing Yang
• Journal: Oncology reports (Oncol Rep) Vol. 25 Issue 2 Pg. 419-24 (Feb 2011) ISSN: 1791-2431 [Electronic] Greece
• PMID: 21152878 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Monocyclic Sesquiterpenes
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Receptors, Tumor Necrosis Factor
• Sesquiterpenes
• humulene
• Caspases

Topics

• Adenocarcinoma (metabolism, pathology)
• Apoptosis (drug effects)
• Caspases (metabolism)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Colorectal Neoplasms (metabolism, pathology)
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical
• HT29 Cells
• Humans
• Models, Biological
• Monocyclic Sesquiterpenes
• Receptors, TNF-Related Apoptosis-Inducing Ligand (metabolism, physiology)
• Receptors, Tumor Necrosis Factor (metabolism, physiology)
• Sesquiterpenes (pharmacology)
• Signal Transduction (physiology)