Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikatacho, Kita-ku, Okayama 700-8558, Japan.
Biochem Biophys Res Commun. 2012 Jul 13;423(4):744-9. doi: 10.1016/j.bbrc.2012.06.030. Epub 2012 Jun 13.
Peritoneal dissemination is one of the most terrible types of colorectal cancer progression. Focal adhesion kinase (FAK) plays a crucial role in the biological processes of cancer, such as cell attachment, migration, proliferation and survival, all of which are essential for the progression of peritoneal dissemination. Since we and other groups have reported that the inhibition of FAK activity exhibited a potent anticancer effect in several cancer models, we hypothesized that TAE226, a novel ATP-competitive tyrosine kinase inhibitor designed to target FAK, can prevent the occurrence and progression of peritoneal dissemination. In vitro, TAE226 greatly inhibited the proliferation and migration of HCT116 colon cancer cells, while their adhesion on the matrix surface was minimally inhibited when FAK activity and expression was suppressed by TAE226 and siRNA. In vivo, when HCT116 cells were intraperitoneally inoculated in mice, the cells could attach to the peritoneum and begin to grow within 24 h regardless of the pretreatment of cells with TAE226 or FAK-siRNA, suggesting that FAK is not essential, at least for the initial integrin-matrix contact. Interestingly, the treatment of mice before and after inoculation significantly suppressed cell attachment to the peritoneum. Furthermore, oral administration of TAE226 greatly reduced the size of disseminated tumors and prolonged survival in tumor-bearing mice. Taken together, a possible strategy for inhibiting peritoneal dissemination by targeting FAK with TAE226 appears to be applicable through anti-proliferative and anti-invasion/anti-migration mechanisms.
腹膜转移是结直肠癌进展最可怕的类型之一。粘着斑激酶（FAK）在癌症的生物学过程中发挥着关键作用，如细胞附着、迁移、增殖和存活，所有这些都是腹膜转移进展所必需的。由于我们和其他小组已经报道，抑制 FAK 活性在几种癌症模型中表现出强大的抗癌作用，我们假设 TAE226，一种新型的 ATP 竞争性酪氨酸激酶抑制剂，旨在靶向 FAK，可以预防腹膜转移的发生和进展。在体外，TAE226 极大地抑制了 HCT116 结肠癌细胞的增殖和迁移，而当 FAK 活性和表达被 TAE226 和 siRNA 抑制时，它们在基质表面的粘附仅受到最小抑制。在体内，当 HCT116 细胞被腹腔内接种到小鼠中时，无论细胞是否用 TAE226 或 FAK-siRNA 预处理，细胞都可以附着在腹膜上并在 24 小时内开始生长，这表明 FAK 不是必需的，至少对于初始整合素-基质接触不是必需的。有趣的是，接种前后对小鼠的治疗显著抑制了细胞对腹膜的附着。此外，口服给予 TAE226 可大大减少播散性肿瘤的大小，并延长荷瘤小鼠的生存时间。总之，通过 TAE226 靶向 FAK 抑制腹膜转移的一种可能策略似乎可通过抗增殖和抗侵袭/抗迁移机制来实现。
