PND-1186 FAK inhibitor selectively promotes tumor cell apoptosis in three-dimensional environments.
PND-1186 FAK inhibitor selectively promotes tumor cell apoptosis in three-dimensional environments.
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DOI：
10.4161/cbt.9.10.11434
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发表时间：
2010-05-15
影响因子：
3.6
通讯作者：
Schlaepfer DD
中科院分区：
文献类型：
--
作者：
Tanjoni I;Walsh C;Uryu S;Tomar A;Nam JO;Mielgo A;Lim ST;Liang C;Koenig M;Sun C;Patel N;Kwok C;McMahon G;Stupack DG;Schlaepfer DD
肿瘤细胞可以以不依赖贴壁的方式生长。这部分是通过生存信号介导的，该信号绕过了整合素细胞表面受体控制的正常生长限制。粘着斑激酶 (FAK) 是一种细胞质蛋白酪氨酸激酶，与整合素结合并调节各种细胞过程，包括生长、存活和迁移。由于 FAK 表达和酪氨酸磷酸化增加与肿瘤进展相关，因此正在测试 FAK 抑制剂的抗肿瘤作用。在这里，我们分析了 PND-1186，一种取代的吡啶可逆 FAK 活性抑制剂，体外 50% 抑制浓度 (IC50) 为 1.5 nM。通过 FAK Tyr-397 的抗磷酸特异性免疫印迹测定，PND-1186 在乳腺癌细胞中的 IC50 约为 100 nM。 PND-1186 不会改变贴壁细胞中的 c-Src 或 p130Cas 酪氨酸磷酸化，但具有抑制细胞运动的作用。 1.0 µM PND-1186（IC50 以上 5 倍以上）对细胞增殖的影响有限，在非贴壁条件下或在软琼脂中生长为球体或菌落时，0.1 µM PND-1186 阻断 FAK 和 p130Cas 酪氨酸磷酸化，促进 caspase-3 激活，并引发细胞凋亡。 PND-1186 抑制 4T1 乳腺癌皮下肿瘤生长，与肿瘤细胞凋亡和 caspase 3 激活增加相关。在小鼠的饮用水中添加 PND-1186 具有良好的耐受性，并能抑制与抑制 FAK 酪氨酸磷酸化相关的腹水相关卵巢癌肿瘤生长。我们的低水平 PND-1186 治疗结果支持以下结论：FAK 活性选择性促进三维环境中肿瘤细胞的存活。
Tumor cells can grow in an anchorage-independent manner. This is mediated in part through survival signals that bypass normal growth restraints controlled by integrin cell surface receptors. Focal adhesion kinase (FAK) is a cytoplasmic protein-tyrosine kinase that associates with integrins and modulates various cellular processes including growth, survival, and migration. As increased FAK expression and tyrosine phosphorylation are associated with tumor progression, inhibitors of FAK are being tested for anti-tumor effects. Here, we analyze PND-1186, a substituted pyridine reversible inhibitor of FAK activity with a 50% inhibitory concentration (IC50) of 1.5 nM in vitro. PND-1186 has an IC50 of ~100 nM in breast carcinoma cells as determined by anti-phospho-specific immunoblotting to FAK Tyr-397. PND-1186 did not alter c-Src or p130Cas tyrosine phosphorylation in adherent cells, yet functioned to restrain cell movement. Whereas 1.0 µM PND-1186 (>5-fold above IC50) had limited effects on cell proliferation, under non-adherent conditions or when grown as spheroids or colonies in soft agar, 0.1 µM PND-1186 blocked FAK and p130Cas tyrosine phosphorylation, promoted caspase-3 activation, and triggered cell apoptosis. PND-1186 inhibited 4T1 breast carcinoma subcutaneous tumor growth correlated with elevated tumor cell apoptosis and caspase 3 activation. Addition of PND-1186 to the drinking water of mice was well tolerated and inhibited ascites-associated ovarian carcinoma tumor growth associated with the inhibition of FAK tyrosine phosphorylation. Our results with low-level PND-1186 treatment support the conclusion that FAK activity selectively promotes tumor cell survival in three-dimensional environments.
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DOI：
10.1083/jcb.200504124
发表时间：
2005-11-07
期刊：
The Journal of cell biology
影响因子：
--
作者：
Benlimame N;He Q;Jie S;Xiao D;Xu YJ;Loignon M;Schlaepfer DD;Alaoui-Jamali MA
通讯作者：
Alaoui-Jamali MA
影响因子：
6
作者：
Provenzano, Paolo P.;Inman, David R.;Keely, Patricia J.
通讯作者：
Keely, Patricia J.
DOI：
10.1083/jcb.200708194
发表时间：
2008-01-14
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lim Y;Lim ST;Tomar A;Gardel M;Bernard-Trifilo JA;Chen XL;Uryu SA;Canete-Soler R;Zhai J;Lin H;Schlaepfer WW;Nalbant P;Bokoch G;Ilic D;Waterman-Storer C;Schlaepfer DD
通讯作者：
Schlaepfer DD
影响因子：
7.8
作者：
Frisch, SM;Vuori, K;Ruoslahti, E;ChanHui, PY
通讯作者：
ChanHui, PY
影响因子：
7.8
作者：
Hungerford, JE;Compton, MT;Matter, ML;Hoffstrom, BG;Otey, CA
通讯作者：
Otey, CA