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Nicotine stimulates urokinase-type plasminogen activator receptor expression and cell invasiveness through mitogen-activated protein kinase and reactive oxygen species signaling in ECV304 endothelial cells.
Toxicol Appl Pharmacol. 2012 Mar 01; 259(2):248-56.TA

Abstract

Urokinase-type plasminogen activator receptor (uPAR) expression is elevated during inflammation, tissue remodeling and in many human cancers. This study investigated the effect of nicotine, a major alkaloid in tobacco, on uPAR expression and cell invasiveness in ECV304 endothelial cells. Nicotine stimulated uPAR expression in a dose-dependent manner and activated extracellular signal-regulated kinases-1/2 (Erk-1/2), c-Jun amino-terminal kinase (JNK) and p38 mitogen activated protein kinase (MAPK). Specific inhibitors of MEK-1 (PD98059) and JNK (SP600125) inhibited the nicotine-induced uPAR expression, while the p38 MAPK inhibitor SB203580 did not. Expression vectors encoding dominant negative MEK-1 (pMCL-K97M) and JNK (TAM67) also prevented nicotine-induced uPAR promoter activity. The intracellular hydrogen peroxide (H(2)O(2)) content was increased by nicotine treatment. The antioxidant N-acetylcysteine prevented nicotine-activated production of reactive oxygen species (ROS) and uPAR expression. Furthermore, exogenous H(2)O(2) increased uPAR mRNA expression. Deleted and site-directed mutagenesis demonstrated the involvement of the binding sites of transcription factor nuclear factor-kappaB (NF-κB) and activator protein (AP)-1 in the nicotine-induced uPAR expression. Studies with expression vectors encoding mutated NF-κB signaling molecules and AP-1 decoy confirmed that NF-κB and AP-1 were essential for the nicotine-stimulated uPAR expression. MAPK (Erk-1/2 and JNK) and ROS functioned as upstream signaling molecules in the activation of AP-1 and NF-κB, respectively. In addition, ECV304 endothelial cells treated with nicotine displayed markedly enhanced invasiveness, which was partially abrogated by uPAR neutralizing antibodies. The data indicate that nicotine induces uPAR expression via the MAPK/AP-1 and ROS/NF-κB signaling pathways and, in turn, stimulates invasiveness in human ECV304 endothelial cells.

Authors+Show Affiliations

Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.No 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

22261521

Citation

Khoi, Pham Ngoc, et al. "Nicotine Stimulates Urokinase-type Plasminogen Activator Receptor Expression and Cell Invasiveness Through Mitogen-activated Protein Kinase and Reactive Oxygen Species Signaling in ECV304 Endothelial Cells." Toxicology and Applied Pharmacology, vol. 259, no. 2, 2012, pp. 248-56.
Khoi PN, Park JS, Kim NH, et al. Nicotine stimulates urokinase-type plasminogen activator receptor expression and cell invasiveness through mitogen-activated protein kinase and reactive oxygen species signaling in ECV304 endothelial cells. Toxicol Appl Pharmacol. 2012;259(2):248-56.
Khoi, P. N., Park, J. S., Kim, N. H., & Jung, Y. D. (2012). Nicotine stimulates urokinase-type plasminogen activator receptor expression and cell invasiveness through mitogen-activated protein kinase and reactive oxygen species signaling in ECV304 endothelial cells. Toxicology and Applied Pharmacology, 259(2), 248-56. https://doi.org/10.1016/j.taap.2012.01.002
Khoi PN, et al. Nicotine Stimulates Urokinase-type Plasminogen Activator Receptor Expression and Cell Invasiveness Through Mitogen-activated Protein Kinase and Reactive Oxygen Species Signaling in ECV304 Endothelial Cells. Toxicol Appl Pharmacol. 2012 Mar 1;259(2):248-56. PubMed PMID: 22261521.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nicotine stimulates urokinase-type plasminogen activator receptor expression and cell invasiveness through mitogen-activated protein kinase and reactive oxygen species signaling in ECV304 endothelial cells. AU - Khoi,Pham Ngoc, AU - Park,Jung Sun, AU - Kim,Nam Ho, AU - Jung,Young Do, Y1 - 2012/01/09/ PY - 2011/10/06/received PY - 2011/12/21/revised PY - 2012/01/02/accepted PY - 2012/1/21/entrez PY - 2012/1/21/pubmed PY - 2012/6/29/medline SP - 248 EP - 56 JF - Toxicology and applied pharmacology JO - Toxicol Appl Pharmacol VL - 259 IS - 2 N2 - Urokinase-type plasminogen activator receptor (uPAR) expression is elevated during inflammation, tissue remodeling and in many human cancers. This study investigated the effect of nicotine, a major alkaloid in tobacco, on uPAR expression and cell invasiveness in ECV304 endothelial cells. Nicotine stimulated uPAR expression in a dose-dependent manner and activated extracellular signal-regulated kinases-1/2 (Erk-1/2), c-Jun amino-terminal kinase (JNK) and p38 mitogen activated protein kinase (MAPK). Specific inhibitors of MEK-1 (PD98059) and JNK (SP600125) inhibited the nicotine-induced uPAR expression, while the p38 MAPK inhibitor SB203580 did not. Expression vectors encoding dominant negative MEK-1 (pMCL-K97M) and JNK (TAM67) also prevented nicotine-induced uPAR promoter activity. The intracellular hydrogen peroxide (H(2)O(2)) content was increased by nicotine treatment. The antioxidant N-acetylcysteine prevented nicotine-activated production of reactive oxygen species (ROS) and uPAR expression. Furthermore, exogenous H(2)O(2) increased uPAR mRNA expression. Deleted and site-directed mutagenesis demonstrated the involvement of the binding sites of transcription factor nuclear factor-kappaB (NF-κB) and activator protein (AP)-1 in the nicotine-induced uPAR expression. Studies with expression vectors encoding mutated NF-κB signaling molecules and AP-1 decoy confirmed that NF-κB and AP-1 were essential for the nicotine-stimulated uPAR expression. MAPK (Erk-1/2 and JNK) and ROS functioned as upstream signaling molecules in the activation of AP-1 and NF-κB, respectively. In addition, ECV304 endothelial cells treated with nicotine displayed markedly enhanced invasiveness, which was partially abrogated by uPAR neutralizing antibodies. The data indicate that nicotine induces uPAR expression via the MAPK/AP-1 and ROS/NF-κB signaling pathways and, in turn, stimulates invasiveness in human ECV304 endothelial cells. SN - 1096-0333 UR - https://www.unboundmedicine.com/medline/citation/22261521/Nicotine_stimulates_urokinase_type_plasminogen_activator_receptor_expression_and_cell_invasiveness_through_mitogen_activated_protein_kinase_and_reactive_oxygen_species_signaling_in_ECV304_endothelial_cells_ DB - PRIME DP - Unbound Medicine ER -