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首页> 外文期刊>Molecular cancer therapeutics >FAK Inhibition Disrupts a beta 5 Integrin Signaling Axis Controlling Anchorage-Independent Ovarian Carcinoma Growth
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FAK Inhibition Disrupts a beta 5 Integrin Signaling Axis Controlling Anchorage-Independent Ovarian Carcinoma Growth

机译：FAK抑制破坏了β5整合素信号轴控制独立于锚地的卵巢癌的生长。

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Ovarian cancer ascites fluid contains matrix proteins that can impact tumor growth via integrin receptor binding. In human ovarian tumor tissue arrays, we find that activation of the cytoplasmic focal adhesion (FAK) tyrosine kinase parallels increased tumor stage, beta 5 integrin, and osteopontin matrix staining. Elevated osteopontin, beta 5 integrin, and FAK mRNA levels are associated with decreased serous ovarian cancer patient survival. FAK remains active within ovarian cancer cells grown as spheroids, and anchorage-independent growth analyses of seven ovarian carcinoma cell lines identified sensitive (HEY, OVCAR8) and resistant (SKOV3-IP, OVCAR10) cells to 0.1 mu mol/L FAK inhibitor (VS-4718, formerly PND-1186) treatment. VS-4718 promoted HEY and OVCAR8 G(0)-G(1) cell-cycle arrest followed by cell death, whereas growth of SKOV3-IP and OVCAR10 cells was resistant to 1.0 mu mol/L VS-4718. In HEY cells, genetic or pharmacological FAK inhibition prevented tumor growth in mice with corresponding reductions in beta 5 integrin and osteopontin expression. beta 5 knockdown reduced HEY cell growth in soft agar, tumor growth in mice, and both FAK Y397 phosphorylation and osteopontin expression in spheroids. FAK inhibitor-resistant (SKOV3-IP, OVCAR10) cells exhibited anchorage-independent Akt S473 phosphorylation, and expression of membrane-targeted and active Akt in sensitive cells (HEY, OVCAR8) increased growth but did not create aFAKinhibitor-resistant phenotype. These results link osteopontin, beta 5 integrin, and FAK in promoting ovarian tumor progression. beta 5 integrin expression may serve as a biomarker for serous ovarian carcinoma cells that possess active FAK signaling. (C) 2014 AACR.
机译：卵巢癌腹水液含有可通过整联蛋白受体结合影响肿瘤生长的基质蛋白。在人类卵巢肿瘤组织阵列中，我们发现细胞质粘着性（FAK）酪氨酸激酶的激活与肿瘤阶段，β5整联蛋白和骨桥蛋白基质染色平行增加。骨桥蛋白，β5整合素和FAK mRNA水平升高与浆液性卵巢癌患者生存率降低相关。 FAK在呈球状生长的卵巢癌细胞中保持活性，对7种卵巢癌细胞系的不依赖于贴壁的生长分析确定了对0.1μmol / L FAK抑制剂（VS -4718，以前是PND-1186）治疗。 VS-4718促进HEY和OVCAR8 G（0）-G（1）细胞周期停滞，随后细胞死亡，而SKOV3-IP和OVCAR10细胞的生长对1.0μmol / L VS-4718具有抗性。在HEY细胞中，遗传或药理FAK抑制作用可阻止小鼠肿瘤的生长，并相应降低β5整合素和骨桥蛋白的表达。 beta 5组合可降低软琼脂中HEY细胞的生长，小鼠中的肿瘤的生长以及球体中FAK Y397的磷酸化和骨桥蛋白的表达。耐FAK抑制剂（SKOV3-IP，OVCAR10）细胞表现出独立于锚定的Akt S473磷酸化，敏感细胞（HEY，OVCAR8）中膜靶向和活性Akt的表达增加了生长，但未产生抗FAK抑制剂的表型。这些结果将骨桥蛋白，β5整合素和FAK促进卵巢肿瘤进展。 β5整合素的表达可能充当具有活跃FAK信号转导的浆液性卵巢癌细胞的生物标志物。 （C）2014 AACR。

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