Watanabe Nobuyuki, Takaoka Munenori, Sakurama Kazufumi, Tomono Yasuko, Hatakeyama Shinji, Ohmori Osamu, Motoki Takayuki, Shirakawa Yasuhiro, Yamatsuji Tomoki, Haisa Minoru, Matsuoka Junji, Beer David G, Nagatsuka Hitoshi, Tanaka Noriaki, Naomoto Yoshio
Department of Gastroenterological Surgery, Okayama University, Okayama, Japan.
Clin Cancer Res. 2008 Jul 15;14(14):4631-9. doi: 10.1158/1078-0432.CCR-07-4755.
Focal adhesion kinase (FAK) regulates integrin and growth factor-mediated signaling pathways to enhance cell migration, proliferation, and survival, and its up-regulation correlates malignant grade and poor outcome in several types of cancer. In this study, we aimed to raise a potential therapeutic strategy using a FAK inhibitor for Barrett's esophageal adenocarcinoma.
The expression status of FAK in clinical Barrett's esophageal adenocarcinoma tissues was determined by immunohistochemistry. Cultured esophageal adenocarcinoma cells were treated with TAE226, a specific FAK inhibitor with an additional effect of inhibiting insulin-like growth factor-I receptor (IGF-IR), to assess its anticancer effect in vitro. Western blot was carried out to explore a participating signaling pathway for TAE226-induced cell death. Furthermore, TAE226 was orally administered to s.c. xenograft animals to investigate its anticancer effect in vivo.
Strong expression of FAK was found in 94.0% of Barrett's esophageal adenocarcinoma compared with 17.9% of Barrett's epithelia, suggesting that FAK might play a critical role in the progression of Barrett's esophageal adenocarcinoma. When esophageal adenocarcinoma cells were treated with TAE226, cell proliferation and migration were greatly inhibited with an apparent structural change of actin fiber and a loss of cell adhesion. The activities of FAK, IGF-IR, and AKT were suppressed by TAE226 and subsequent dephosphorylation of BAD at Ser(136) occurred, resulting in caspase-mediated apoptosis. In vivo tumor volume was significantly reduced by oral administration of TAE226.
These results suggest that TAE226, a dual tyrosine kinase inhibitor for FAK and IGF-IR, could become a new remedy for Barrett's esophageal adenocarcinoma.
粘着斑激酶（FAK）调节整合素和生长因子介导的信号通路，以增强细胞迁移、增殖和存活，其上调与几种癌症的恶性程度和不良预后相关。在本研究中，我们旨在提出一种使用FAK抑制剂治疗巴雷特食管腺癌的潜在策略。
通过免疫组织化学确定临床巴雷特食管腺癌组织中FAK的表达状态。用TAE226处理培养的食管腺癌细胞，TAE226是一种特异性FAK抑制剂，还具有抑制胰岛素样生长因子-I受体（IGF-IR）的作用，以评估其体外抗癌效果。进行蛋白质印迹法以探索TAE226诱导细胞死亡的参与信号通路。此外，将TAE226口服给予皮下异种移植动物，以研究其体内抗癌效果。
在94.0%的巴雷特食管腺癌中发现FAK强表达，而在巴雷特上皮中为17.9%，这表明FAK可能在巴雷特食管腺癌的进展中起关键作用。当用TAE226处理食管腺癌细胞时，细胞增殖和迁移受到极大抑制，肌动蛋白纤维出现明显结构变化且细胞粘附丧失。TAE226抑制了FAK、IGF-IR和AKT的活性，随后BAD在Ser(136)处发生去磷酸化，导致半胱天冬酶介导的细胞凋亡。口服TAE226可使体内肿瘤体积显著减小。
这些结果表明，TAE226作为一种针对FAK和IGF-IR的双酪氨酸激酶抑制剂，可能成为巴雷特食管腺癌的一种新疗法。
