ToxSci Advance Access published online on November 3, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp259
Cadmium Induces Intracellular Ca2+- and H2O2-dependent Apoptosis through JNK- and p53-mediated Pathways in Skin Epidermal Cell line
* Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0305, USA # School of Dentistry and 21 Century Education Center for Advanced Public Dental Health (BK 21 program), Research Center of Bioactive Materials, Chonbuk National University, Jeonju 561-756, South Korea
1 Address corresponding to: Xianglin Shi, Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KY 40536-0305. Tel: 859-257-4054; Fax: 859-323-1059; E-mail: xshi5{at}email.uky.edu
Received August 10, 2009; revision received September 19, 2009; accepted October 18, 2009
 |
Abstract |
|---|
Cadmium is a toxic heavy metal and has been widely used in industry. The skin is an important target for this metal. The mechanisms by which cadmium leads to damage to the skin are unclear at present. The aims of this study were to examine whether cadmium induces apoptosis in mouse skin epidermal cell line, JB6 Cl41 cells, and to investigate the cellular mechanisms by which cadmium causes cytotoxicity in the cells. The present study showed that cadmium induced cell death by apoptosis in a dose-dependent manner, as proven by the appearance of cell shrinkage, the increase of Annexin V-positively stained cells, and the formation of nuclear DNA ladders. Cadmium-induced apoptosis involved a mitochondria-mediated mechanism but not caspase-dependent pathway, in that the critical apoptotic events induced by cadmium, such as the decrease of Bcl-2/Bcl-xL, the increase of GADD45
, and the nuclear translocation of AIF, were not affected by the inhibition of executive caspases. In contrast, blockage of p53 and JNK by pharmacological inhibitors or si-RNA transfection suppressed the cadmium-induced apoptosis with the concomitant inhibition of anti-apoptotic Bcl-2 family proteins and GADD45, respectively. Further, the activation of p53 and JNK and their downstream proteins in cadmium-exposed cells were inhibited by individual treatment with catalase and Bapta-AM. These results suggest that cadmium induces apoptosis via the activation of JNK- and p53-mediated signaling, where calcium ion and hydrogen peroxide act as the pivotal mediators of the apoptotic signaling.
Key Words: Cadmium; Skin epidermal cell; Cytotoxicity; Apoptosis; p53; JNK.