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Pyrrolidine dithiocarbamate (PDTC)/Cu complex induces lung epithelial cell apoptosis through mitochondria and ER-stress pathways.
Toxicol Lett. 2010 Dec 15; 199(3):333-40.TL

Abstract

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, CuCl(2), 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 CuCl(2) 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 CuCl(2) 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.

Authors+Show Affiliations

Department of Physiology, and Graduate Institute of Basic Medical Science, College of Medicine, China Medical University, No. 91 Hsueh-Shih Road, Taichung 40402, Taiwan. ywc@mail.cmu.edu.twNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20920558

Citation

Chen, Ya-Wen, et al. "Pyrrolidine Dithiocarbamate (PDTC)/Cu Complex Induces Lung Epithelial Cell Apoptosis Through Mitochondria and ER-stress Pathways." Toxicology Letters, vol. 199, no. 3, 2010, pp. 333-40.
Chen YW, Chen KL, Chen CH, et al. Pyrrolidine dithiocarbamate (PDTC)/Cu complex induces lung epithelial cell apoptosis through mitochondria and ER-stress pathways. Toxicol Lett. 2010;199(3):333-40.
Chen, Y. W., Chen, K. L., Chen, C. H., Wu, H. C., Su, C. C., Wu, C. C., Way, T. D., Hung, D. Z., Yen, C. C., Yang, Y. T., & Lu, T. H. (2010). Pyrrolidine dithiocarbamate (PDTC)/Cu complex induces lung epithelial cell apoptosis through mitochondria and ER-stress pathways. Toxicology Letters, 199(3), 333-40. https://doi.org/10.1016/j.toxlet.2010.09.016
Chen YW, et al. Pyrrolidine Dithiocarbamate (PDTC)/Cu Complex Induces Lung Epithelial Cell Apoptosis Through Mitochondria and ER-stress Pathways. Toxicol Lett. 2010 Dec 15;199(3):333-40. PubMed PMID: 20920558.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pyrrolidine dithiocarbamate (PDTC)/Cu complex induces lung epithelial cell apoptosis through mitochondria and ER-stress pathways. AU - Chen,Ya-Wen, AU - Chen,Kuo-Liang, AU - Chen,Chun-Hung, AU - Wu,Hsi-Chin, AU - Su,Chin-Chuan, AU - Wu,Chin-Ching, AU - Way,Tzong-Der, AU - Hung,Dong-Zong, AU - Yen,Cheng-Chien, AU - Yang,Yuan-Ting, AU - Lu,Tien-Hui, Y1 - 2010/11/02/ PY - 2010/08/23/received PY - 2010/09/23/revised PY - 2010/09/24/accepted PY - 2010/10/6/entrez PY - 2010/10/6/pubmed PY - 2010/12/18/medline SP - 333 EP - 40 JF - Toxicology letters JO - Toxicol Lett VL - 199 IS - 3 N2 - 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, CuCl(2), 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 CuCl(2) 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 CuCl(2) 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. SN - 1879-3169 UR - https://www.unboundmedicine.com/medline/citation/20920558/Pyrrolidine_dithiocarbamate__PDTC_/Cu_complex_induces_lung_epithelial_cell_apoptosis_through_mitochondria_and_ER_stress_pathways_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-4274(10)01704-2 DB - PRIME DP - Unbound Medicine ER -