Anti-tumor effect of a novel FAK inhibitor TAE226 against human oral squamous cell carcinoma
Anti-tumor effect of a novel FAK inhibitor TAE226 against human oral squamous cell carcinoma
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DOI：
10.1016/j.oraloncology.2012.05.019
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发表时间：
2012-11-01
期刊：
影响因子：
4.8
通讯作者：
Sasaki, Akira
中科院分区：
文献类型：
--
作者：
Kurio, Naito;Shimo, Tsuyoshi;Sasaki, Akira
目的：粘着斑激酶（FAK）过度表达常见于浸润性和转移性肿瘤，但其在口腔鳞状细胞癌中的作用尚不清楚。为寻求针对口腔鳞癌的治疗方法，我们研制了新型FAK Tyr（397）抑制剂TAE226，并对其抗肿瘤作用及机制进行了研究。结果：TAE 226对人舌鳞癌细胞增殖、细胞周期、细胞凋亡及血管生成的影响均得到证实。重要的是，TAE 226极大地抑制了人口腔鳞状细胞癌SAS细胞的增殖、迁移和侵袭，其肌动蛋白纤维的结构发生明显变化，细胞粘附能力丧失。此外，TAE226抑制磷酸化FAK Tyr（397）和磷酸化AKT Ser（473）的表达，导致caspase介导的细胞凋亡。此外，小鼠口服给药的TAE226抑制口腔鳞状细胞癌异种移植物的生长和血管生成在vivo.Conclusions：我们的研究结果提供了令人信服的证据表明，FAK是至关重要的参与口腔鳞状细胞癌和FAK抑制剂TAE226可以有效地用于治疗口腔鳞状细胞癌。(C)2012爱思唯尔有限公司保留所有权利。
Objectives: Focal adhesion kinase (FAK) overexpression is frequently found in invasive and metastatic cancers, but its role in oral squamous cell carcinoma is not yet well understood. In order to seek therapies targeting oral squamous cell carcinoma, we developed the novel FAK Tyr(397) inhibitor TAE226 and investigated its anti-tumor effects and mechanisms.Materials and Methods: Expression of phosphorylated FAK Tyr(397) was examined by immunohistochemical and immunoblot analysis. The effect of TAE226 on in vitro and in vivo studies were confirmed by proliferation, cell cycle, apoptosis and angiogenesis analysis.Results: We found that phosphorylated FAK was highly expressed in human tongue oral squamous cell carcinoma in patients. Importantly, TAE226 greatly suppressed the proliferation, migration and invasion of human oral squamous cell carcinoma SAS cells with an apparent structural change of actin fiber and a loss of cell adhesion. In addition, TAE226 inhibited the expression of phospho-FAK Tyr(397) and phospho AKT Ser(473), resulting in caspase-mediated apoptosis. Furthermore, oral administration of TAE226 in mice suppressed the growth and angiogenesis of oral squamous cell carcinoma xenografts in vivo.Conclusions: Our results provide compelling evidence that FAK is critically involved in oral squamous cell carcinoma and that the FAK inhibitor TAE226 can potentially be effectively used for the treatment of oral squamous cell carcinoma. (C) 2012 Elsevier Ltd. All rights reserved.