Alantolactone induces cell apoptosis partially through down-regulation of testes-specific protease 50 expression.

Abstract

Testes-specific protease 50 (TSP50) is aberrantly expressed in many cancer biopsies and plays a crucial role in tumorigenesis, which make it a potential cancer therapeutic target for drug discovery. Here, we constructed a firefly luciferase reporter driven by the TSP50 gene promoter to screen natural compounds capable of inhibiting the expression of TSP50. Then we identified alantolactone, a sesquiterpene lactone, could efficiently inhibit the promoter activity of TSP50 gene, further results revealed that alantolactone also efficiently inhibited the expression of TSP50 in both mRNA and protein levels. Moreover, we found alantolactone could increase the ratio of Bax/Bcl-2, and activate caspase-9 and caspase-3 in the cancer cells with high expression of TSP50, surprisingly, the same effects can also be observed in the same cells just by knockdown of TSP50 gene expression. Furthermore, our results suggested that overexpression of TSP50 decreased the cell sensitivity to alantolactone-induced apoptosis in those cancer cells. Taken together, these results suggest that alantolactone induces mitochondrial-dependent apoptosis at least partially via down-regulation of TSP50 expression.

• Authors: Xu-Guang Mi, Zhen-Bo Song, Ping Wu, Yu-Wei Zhang, Lu-Guo Sun, Yong-Li Bao, Yu Zhang, Li-Hua Zheng, Ying Sun, Chun-Lei Yu, Yin Wu, Guan-Nan Wang, Yu-Xin Li
• Journal: Toxicology letters (Toxicol Lett) Vol. 224 Issue 3 Pg. 349-55 (Jan 30 2014) ISSN: 1879-3169 [Electronic] Netherlands
• PMID: 24252419 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antifungal Agents
• Lactones
• Proto-Oncogene Proteins c-bcl-2
• Sesquiterpenes, Eudesmane
• bcl-2-Associated X Protein
• RNA
• Serine Endopeptidases
• testis-specific protease 50
• Caspase 3
• Caspase 9
• alantolactone

Topics

• Antifungal Agents (toxicity)
• Apoptosis (drug effects)
• Blotting, Western
• Caspase 3 (biosynthesis)
• Caspase 9 (biosynthesis)
• Cell Line, Tumor
• Cell Membrane (drug effects, ultrastructure)
• Down-Regulation (drug effects)
• Humans
• Lactones (toxicity)
• Male
• Mitochondria (drug effects, metabolism)
• Plasmids (genetics)
• Promoter Regions, Genetic (drug effects)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• RNA (biosynthesis, isolation & purification)
• Real-Time Polymerase Chain Reaction
• Serine Endopeptidases (biosynthesis, drug effects, genetics)
• Sesquiterpenes, Eudesmane (toxicity)
• Transfection
• bcl-2-Associated X Protein (genetics, metabolism)