Role of Calmodulin in the Generation of Reactive Oxygen Species and Apoptosis Induced by Tamoxifen in HepG2 Human Hepatoma Cells.
- Author:
Yong Soo LEE
1
Author Information
1. College of Pharmacy, Duksung Women's University, Seoul, Korea. yongslee@duksung.ac.kr
- Publication Type:Original Article
- Keywords:
Calmodulin;
Ca2+/calmodulin-dependent protein kinase II;
Tamoxifen;
Apoptosis;
Reactive oxygen species;
HepG2 cell
- MeSH:
Apoptosis*;
Calcium-Calmodulin-Dependent Protein Kinase Type 2;
Calmodulin*;
Carcinoma, Hepatocellular*;
Estrogen Receptor Modulators;
Hep G2 Cells;
Hepatoblastoma;
Humans*;
Protein Kinases;
Reactive Oxygen Species*;
Receptors, Estrogen;
Tamoxifen*
- From:The Korean Journal of Physiology and Pharmacology
2002;6(4):187-192
- CountryRepublic of Korea
- Language:English
-
Abstract:
Tamoxifen, an antiestrogen, has previously been shown to induce apoptosis in HepG2 human hepatoblastoma cells through activation of the pathways independent of estrogen receptors, i.e., intracellular Ca2+ increase and generation of reactive oxygen species (ROS). However, the mechanism of tamoxifen to link increased intracellular Ca2+ to ROS generation is currently unknown. Thus, in this study we investigated the possible involvement of calmodulin, a Ca2+ activated protein, and Ca2+/ calmodulin-dependent protein kinase II in the above tamoxifen-induced events. Treatment with calmodulin antagonists (calmidazolium and trifluoroperazine) or specific inhibitors of Ca2+/calmodulin-dependent protein kinase II (KN-93 and KN-62) inhibited the tamoxifen-induced apoptosis in a dose-dependent manner. In addition, these agents blocked the tamoxifen-induced ROS generation in a concentration-dependent fashion, which was completely suppressed by intracellular Ca2+ chelation. These results demonstrate for the first time that, despite of its well-known direct calmodulin-inhibitory activity, tamoxifen may generate ROS and induce apoptosis through indirect activation of calmodulin and Ca2+/calmodulin-dependent protein kinase II in HepG2 cells.
