セツキシマブ耐性口腔扁平上皮癌細胞は足場非依存性増殖条件下においてEGFR/AKT伝達経路の活性化を介して感受性を得る

• Published in: 日本口腔外科学会雑誌 Vol. 62; no. 9; pp. 476 - 486
• Main Authors: 野崎, 正美, 大西, 祐一, 覚道, 健治, 安井, 大樹
• Format: Journal Article
• Language: Japanese
• Published: 社団法人 日本口腔外科学会 20.09.2016
• Subjects: EGFレセプター; セツキシマブ; 細胞塊形成; 細胞増殖; 細胞遊走
• ISSN: 0021-5163; 2186-1579
• DOI: 10.5794/jjoms.62.476

We have previously shown that growth of the oral squamous cell carcinoma cell line SAS is resistant to cetuximab in monolayer culture conditions even though epidermal growth factor receptor (EGFR) was phosphorylated, whereas growth of SAS aggregates was sensitive to cetuximab. In the present study, we demonstrate differences in the EGFR signaling pathways utilized by SAS cells in monolayer and suspension cultures at the molecular level. Cetuximab treatment of SAS cells in monolayer cultures inhibits the phosphorylation of EGFR and ERK and reduces the cell migratory potency, but not cell proliferation. AG1478 treatment reduces the phosphorylation of EGFR, ERK, and AKT, and affects cell growth in monolayer cultures. The phosphorylation levels of EGFR and AKT are significantly higher in SAS cell aggregates than in monolayer cultures. Treatment with cetuximab and AG1478 reduces the growth of SAS aggregates and eliminates the phosphorylation of EGFR and AKT. Furthermore, proliferation of SAS aggregates is also inhibited by LY294002 and MK2206, which are inhibitors of PI3K and AKT, respectively. In addition, treatment with the lipid raft disruptor filipin III reduced the phosphorylation levels of EGFR and Akt in SAS aggregates, but not in SAS monolayer cultures. These results suggest that ligands in the serum stimulate the phosphorylation of EGFR localized in lipid rafts, leading to PI3K-AKT activation, which results in the growth of SAS aggregates, potentially increasing the sensitivity of SAS aggregates to cetuximab.