Functions of epidermal growth factor receptor in cisplatin response of thyroid cells.
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.
Muscella
Antonella
A
Department of Biological and Environmental Sciences and Technologies (Di.S.Te.B.A.), Università del Salento, via Prov.le per Monteroni, 73100 Lecce, Italy.
Urso
Loredana
L
Calabriso
Nadia
N
Vetrugno
Carla
C
Fanizzi
Francesco Paolo
FP
Storelli
Carlo
C
Marsigliante
Santo
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D011799:Quinazolines; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013961:Thyroid Gland / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology
D011799:Quinazolines; D017382:Reactive Oxygen Species; D020032:Tyrphostins; C101044:RTKI cpd; D066246:ErbB Receptors; D048051:p38 Mitogen-Activated Protein Kinases; D002945:Cisplatin