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KMID : 0603820140200020085
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Journal of Experimental & Biomedical Science
2014 Volume.20 No. 2 p.85 ~ p.95
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The GSK-3β/Cyclin D1 Pathway is Involved in the Resistance of Oral Cancer Cells to the EGFR Tyrosine Kinase Inhibitor ZD1839
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Jeon Nam-Kyeong
Kim Jin
Lee Eun-Ju
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Abstract
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Activation of the epidermal growth factor receptor (EGFR) and downstream signaling pathways have been implicated in causing resistance to EGFR-targeted therapy in solid tumors, including the head and neck tumors. To investigate the mechanism of antiproliferation to EGFR inhibition in oral cancer, we compared EGFR tyrosine kinase inhibitor (Gefitinib, Iressa, ZD1839) with respect to its inhibitory effects on three kinases situated downstream of EGFR: MAPK, Akt, and glycogen synthase kinase-3β (GSK-3β). We have demonstrated that ZD1839 induces growth arrest and apotosis in oral cancer cell lines by independent of EGFR-mediated signaling. An exposure of oral cancer cells to ZD1839 resulted in a dose dependent up-regulation of the cyclin-dependent kinase inhibitor p21 and p27, down regulation of cyclin D1, inactivation of GSK-3β and of active MAPK. In resistant cells, GSK-3β is constitutively active and its activity is negatively regulated primarily through Ser 9 phosphorylation and further enhanced by Tyr216 phosphorylation. These results showed that the resistance to the antiproliferative effects of ZD1839, in vitro was associated with uncoupling between EGFR and MAPK inhibition, and that GSK-3β activation and degradation of its target cyclin D1 were indicators of high cell sensitivity to ZD1839. In conclusion, our data show that the uncoupling of EGFR with mitogenic pathways can cause resistance to EGFR inhibition in oral cancer.
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KEYWORD
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Cyclin D1, Glycogen synthase kinase-3β, Human oral carcinoma cells, p21CIP1/WAF1, p27KIP1, ZD1839
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