Inhibition of focal adhesion kinase (FAK) activity prevents anchorage-independent ovarian carcinoma cell growth and tumor progression.
Inhibition of focal adhesion kinase (FAK) activity prevents anchorage-independent ovarian carcinoma cell growth and tumor progression.
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DOI：
10.1007/s10585-012-9562-5
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发表时间：
2013-06
影响因子：
4
通讯作者：
Schlaepfer DD
中科院分区：
文献类型：
--
作者：
Ward KK;Tancioni I;Lawson C;Miller NL;Jean C;Chen XL;Uryu S;Kim J;Tarin D;Stupack DG;Plaxe SC;Schlaepfer DD
卵巢癌的复发和扩散是美国女性死亡的第五大原因。粘着斑激酶（FAK）是一种位于染色体8q24.3（基因为Ptk 2）的胞浆蛋白酪氨酸激酶，该位点通常在浆液性卵巢癌中扩增。浆液性卵巢癌中FAK mRNA水平升高与患者总生存率降低相关（logrank P = 0.0007，风险比1.43），但FAK在肿瘤进展中的作用尚不明确。我们在C57 B16小鼠中腹膜内（IP）生长鼠ID 8细胞后分离了称为ID 8-IP的侵袭性卵巢癌细胞。在卵巢周围囊空间内原位植入后，与亲本ID 8细胞相比，ID 8-IP细胞表现出更大的肿瘤生长、局部和远处转移以及升高的腹水相关细胞数量。与亲本ID 8细胞相比，ID 8-IP细胞在非粘附条件下表现出增强的生长，具有升高的FAK和c-Src酪氨酸激酶活化。在体外，0.1 μ M的小分子FAK抑制剂（Pfizer，PF 562，271，PF-271）选择性地阻止锚定非依赖性ID 8-IP细胞生长，抑制FAK酪氨酸（Y）397但不抑制c-Src Y 416磷酸化。在ID 8-IP肿瘤中，PF-271口服给药（30 mg/kg，每日两次）可阻断FAK，但不能阻断c-Src酪氨酸磷酸化。这与肿瘤大小减小、腹膜转移预防、肿瘤相关内皮细胞数量减少和肿瘤细胞相关凋亡增加有关。FAK敲低和再表达测定显示FAK活性选择性地促进锚定非依赖性ID 8-IP细胞存活。这些结果支持继续评估FAK抑制剂作为卵巢癌有前途的临床治疗。
Recurrence and spread of ovarian cancer is the 5th leading cause of death for women in the United States. Focal adhesion kinase (FAK) is a cytoplasmic protein-tyrosine kinase located on chromosome 8q24.3 (gene is Ptk2), a site commonly amplified in serous ovarian cancer. Elevated FAK mRNA levels in serous ovarian carcinoma are associated with decreased (logrank P = 0.0007, hazard ratio 1.43) patient overall survival, but how FAK functions in tumor progression remains undefined. We have isolated aggressive ovarian carcinoma cells termed ID8-IP after intraperitoneal (IP) growth of murine ID8 cells in C57Bl6 mice. Upon orthotopic implantation within the periovarian bursa space, ID8-IP cells exhibit greater tumor growth, local and distant metastasis, and elevated numbers of ascites-associated cells compared to parental ID8 cells. ID8-IP cells exhibit enhanced growth under non-adherent conditions with elevated FAK and c-Src tyrosine kinase activation compared to parental ID8 cells. In vitro, the small molecule FAK inhibitor (Pfizer, PF562,271, PF-271) at 0.1 uM selectively prevented anchorage-independent ID8-IP cell growth with the inhibition of FAK tyrosine (Y)397 but not c-Src Y416 phosphorylation. Oral PF-271 administration (30 mg/kg, twice daily) blocked FAK but not c-Src tyrosine phosphorylation in ID8-IP tumors. This was associated with decreased tumor size, prevention of peritoneal metastasis, reduced tumor-associated endothelial cell number, and increased tumor cell-associated apoptosis. FAK knockdown and re-expression assays showed that FAK activity selectively promoted anchorage-independent ID8-IP cell survival. These results support the continued evaluation of FAK inhibitors as a promising clinical treatment for ovarian cancer.
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DOI：
10.1038/nrc2644
发表时间：
2009-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
16
作者：
Lim, Ssang-Taek;Chen, Xiao Lei;Llic, Dusko
通讯作者：
Llic, Dusko
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
10.5
作者：
McLean, GW;Komiyama, NH;Frame, MC
通讯作者：
Frame, MC
影响因子：
6.2
作者：
Bagi, Cedo M.;Roberts, Gregory W.;Andresen, Catharine J.
通讯作者：
Andresen, Catharine J.