| Functions of epidermal growth factor receptor in cisplatin response of thyroid cells. | |
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MedLine Citation:
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PMID: 19111676 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Epidermal growth factor receptor (EGFR) signal transduction pathway has been reported to play a vital role in the biologic progression of several tumours and as targets for therapeutic intervention. We have investigated the role of EGFR in the thyroid PC Cl3 cells response to the chemo-therapeutic agent cisplatin. It was found that cisplatin provoked (1) the activation (phosphorylation) and internalization of EGFR, (2) the phosphorylation of mitogen-activated protein kinase (MAPK)/p38, (3) the activation of PKC-epsilon, (4) the enhancement of matrix metalloproteinase-2 (MMP-2) expression and activity, (5) the generation of reactive oxygen species (ROS) and (6) the activation of the apoptotic intrinsic pathway. Inhibition or down regulation of EGFR reduced (1) the phosphorylation of MAPK/p38, (2) the cisplatin-provoked activation of PKC-epsilon, and (3) the activation of caspase-7 and PARP cleavage and the overall cells sensitivity to cisplatin. PKC-epsilon inhibition achieved by siRNA blocked MAPK/p38 activation and significantly increased the cell resistance to cisplatin. Finally, when the cisplatin-induced ROS generation was blocked by using NAD(P)H oxidase inhibitors, a decrease in cisplatin-induced MMP-2 enhancement, MAPK/p38 and EGFR activation, and caspase-7 proteolysis occurred. In conclusion, these findings supported a model in which cisplatin provokes an oxidant-induced MMP-2-dependent EGFR transactivation responsible for the induction of cell apoptosis, a process ascribable to the intracellular signalling of PKC-epsilon and MAPK/p38. |
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Authors:
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Antonella Muscella; Loredana Urso; Nadia Calabriso; Carla Vetrugno; Francesco Paolo Fanizzi; Carlo Storelli; Santo Marsigliante |
Publication Detail:
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Type: Comparative Study; Journal Article Date: 2008-12-06 |
Journal Detail:
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Title: Biochemical pharmacology Volume: 77 ISSN: 1873-2968 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 2009 Mar |
Date Detail:
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Created Date: 2009-03-02 Completed Date: 2009-04-01 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 979-92 Citation Subset: IM |
Affiliation:
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Department of Biological and Environmental Sciences and Technologies (Di.S.Te.B.A.), Università del Salento, via Prov.le per Monteroni, 73100 Lecce, Italy. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / drug effects, physiology Cell Line Cisplatin / pharmacology* Dose-Response Relationship, Drug Rats Reactive Oxygen Species / metabolism Receptor, Epidermal Growth Factor / antagonists & inhibitors, metabolism, physiology* Signal Transduction / drug effects, physiology Thyroid Gland / cytology, drug effects*, enzymology, metabolism* Tyrphostins / pharmacology p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors, physiology |
| Chemical | |
Reg. No./Substance:
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0/Reactive Oxygen Species; 0/Tyrphostins; 15663-27-1/Cisplatin; 170449-18-0/tyrphostin AG 1478; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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