Pyrrolidine dithiocarbamate (PDTC)/Cu complex induces lung epithelial cell apoptosis through mitochondria and ER-stress pathways
| Autor: | Yuan Ting Yang, Ya-Wen Chen, Chin-Chuan Su, Chin Ching Wu, Dong-Zong Hung, Kuo-Liang Chen, Tzong Der Way, Hsi Chin Wu, Tien Hui Lu, Cheng Chien Yen, Chun-Hung Chen |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Cell signaling
Pyrrolidines Cell Survival p38 mitogen-activated protein kinases Apoptosis Biology Endoplasmic Reticulum Toxicology Cell Line chemistry.chemical_compound Pyrrolidine dithiocarbamate Thiocarbamates Animals Protein phosphorylation Viability assay Phosphorylation Lung Cytochrome c JNK Mitogen-Activated Protein Kinases Epithelial Cells General Medicine Mitochondria Rats Cell biology Cytosol Proto-Oncogene Proteins c-bcl-2 chemistry Biochemistry Caspases biology.protein Copper Signal Transduction |
| Zdroj: | Toxicology Letters. 199:333-340 |
| ISSN: | 0378-4274 |
| Popis: | Pyrrolidine dithiocarbamate (PDTC) is widely used in pesticides, fungicides, insecticides, and herbicides. Copper (Cu) is a toxic heavy metal in the environment, and an essential trace metal element in the body, which is involved in many biological processes as a catalytic cofactor. The present study is designed to investigate the cellular toxicity of PDTC, CuCl2, and PDTC/Cu complex exposure in lung alveolar epithelial cells that serve primary structural and functional roles in the lungs. The results showed that PDTC or CuCl2 alone did not affect cell viability, but PDTC/Cu complex significantly decreased lung alveolar epithelial cell viability. PDTC/Cu complex also significantly increased intracellular copper concentration, but PDTC or CuCl2 alone had low levels of copper. PDTC/Cu complex dramatically enhanced the JNK protein phosphorylation and ERK protein phosphorylation proteins. PDTC/Cu complex did not affect the p38 protein phosphorylation. PDTC/Cu complex was capable of activating the apoptosis-related caspases including caspase-9, caspase-7, and caspase-3, which could be reversed by the addition of JNK inhibitor SP600125 or transfection of MAPK8 short hairpin RNA. PDTC/Cu complex also increased cytosolic cytochrome c and decreased mitochondrial transmembrane potential. The Bcl-2 mRNA and protein expressions were decreased in lung epithelial cells treated with PDTC/Cu complex, which could be reversed by SP600125. Furthermore, PDTC/Cu complex could trigger the expressions of ER stress-associated signaling molecules including Grp78, Grp94, caspase-12, ATF4, and CHOP, which could be reversed by SP600125. Taken together, these results indicate that exposure to PDTC/Cu complex induces cytotoxicity and apoptosis in alveolar epithelial cells via the mitochondria- and ER-stress-related signaling pathways. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect