Korean J Physiol Pharmacol.  2002 Aug;6(4):187-192.

Role of Calmodulin in the Generation of Reactive Oxygen Species and Apoptosis Induced by Tamoxifen in HepG2 Human Hepatoma Cells

• Lee YS

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.

Keyword

Calmodulin; Ca2+/calmodulin-dependent protein kinase II; Tamoxifen; Apoptosis; Reactive oxygen species; HepG2 cell

MeSH Terms

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*
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Calmodulin
Estrogen Receptor Modulators
Protein Kinases
Reactive Oxygen Species
Receptors, Estrogen
Tamoxifen