2012 Fiscal Year Final Research Report
A Nobel strategy for head and neck cancer by internalization of epidermal growth factor receptor
| Project/Area Number |
22591910
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Otorhinolaryngology
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| Research Institution | Kyushu University |
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Principal Investigator |
TOH Satoshi 九州大学, 大学病院, 講師 (20380397)
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| Co-Investigator(Kenkyū-buntansha) |
NAKASHIMA Torahiko 九州大学, 医学研究院, 准教授 (00284505)
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| Project Period (FY) |
2010 – 2012
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| Keywords | 頭頚部外科学 |
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| Research Abstract |
RGFR is expressing in various carcimona cells and plays critical roles of ploriferation, invasion and metastasis. Some molecular targeting drugs against EGFR are already applied for cancer patients. In this study, we investigated a mechanism of internalization of EGFR as novel strategy of targeting EGFR pathway.Although the precise mechanism of ligand-induced EGFR internalization is still unclear, some reports suggest that a src family non-receptor tyrosine kinase (SFK) may play a role in this process. Therefore, we hypothesized that a src family kinase may also play a role in EGCG-induced EGFR internalization. Using YCU-H891 cells, we conducted a time course study and found that EGCG can activate c-src in a doseand time-dependent manner. Activation was detected with as low as 1μM of EGCG and within 10min. This time course is consistent with our previous findings that EGCG can induce EGFR internalization within 30 min. Next, we investigated the effect of EGCG on the level of cell surface EGFR using a quantitative ELISA assay, and found that EGCG 40μM causes a significant decrease in the amount of cell surface EGFR. This reduction was partially rescued by the src kinase specific inhibitor PP1. We confirmed these findings using fluorescence microscopy by demonstrating that combined treatment with EGCG and PP1 decreased the amount of internalized vesicles containing EGFR.c-Src is anchoring to plasma membrane through its N-terminal acyl group. EGCGalternate lipid organization of plasma membrane, therefore we investigated whetherc-src is essential for internalization of EGFR. Inhibition of N-treminal acylation effectively reduce phosphorylation of c-src and also inhibited EGCG induced EGFR internalization. Taken together with these findings, alternation of lipid organization could regulate EGFR internalization through c-src activation.
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