Inhibition of pressure-activated cancer cell adhesion by FAK-derived peptides.
Inhibition of pressure-activated cancer cell adhesion by FAK-derived peptides.
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DOI：
10.18632/oncotarget.20556
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发表时间：
2017-11-17
期刊：
影响因子：
--
通讯作者：
Basson MD
中科院分区：
文献类型：
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作者：
Zeng B;Devadoss D;Wang S;Vomhof-DeKrey EE;Kuhn LA;Basson MD
手术环境或循环中的力通过需要FAK-Akt 1相互作用的信号传导激活癌细胞粘附并增强转移。阻碍FAK-AKT 1相互作用可能会抑制围手术期肿瘤扩散，促进治愈性癌症手术，而没有整体FAK或AKT抑制剂毒性。FAK的系列截短和结构设计突变体鉴定了FAK内的七个氨基酸的短螺旋结构，其有效地与Akt 1-FAK相互作用竞争。这种FAK衍生肽的腺病毒过表达抑制了短暂暴露于15 mmHg升高压力的人SW 620结肠癌细胞中压力诱导的FAK磷酸化和AKT-FAK共免疫沉淀，与腹腔镜或手术后压力一致。腺病毒FAK衍生肽表达不仅阻止SW 620粘附到胶原蛋白-I-包被的板，而且也阻止SW 620粘附到鼠手术伤口的压力激活。而乱序肽则不然。最后，我们通过在冲洗和闭合之前暂时癌细胞粘附到小鼠手术伤口来模拟在冲洗和闭合之前肿瘤细胞的手术脱落。在15 mmHg压力下预孵育SW 620细胞30分钟，增加的压力损害了暴露于表达乱序肽的细胞的小鼠随后的无肿瘤存活。FAK衍生序列阻止了这一点。这些结果表明，阻断FAK-Akt 1相互作用可以防止围手术期肿瘤扩散，并且这种7个氨基酸的FAK衍生肽的类似物或模拟物可以损害转移。
Forces within the surgical milieu or circulation activate cancer cell adhesion and potentiate metastasis through signaling requiring FAK-Akt1 interaction. Impeding FAK-Akt1 interaction might inhibit perioperative tumor dissemination, facilitating curative cancer surgery without global FAK or AKT inhibitor toxicity. Serial truncation and structurally designed mutants of FAK identified a seven amino acid, short helical structure within FAK that effectively competes with Akt1-FAK interaction. Adenoviral overexpression of this FAK-derived peptide inhibited pressure-induced FAK phosphorylation and AKT-FAK coimmunoprecipitation in human SW620 colon cancer cells briefly exposed to 15mmHg increased pressure, consistent with laparoscopic or post-surgical pressures. Adenoviral FAK-derived peptide expression prevented pressure-activation of SW620 adhesion not only to collagen-I-coated plates but also to murine surgical wounds. A scrambled peptide did not. Finally, we modeled operative shedding of tumor cells before irrigation and closure by transient cancer cell adhesion to murine surgical wounds before irrigation and closure. Thirty minute preincubation of SW620 cells at 15mmHg increased pressure impaired subsequent tumor free survival in mice exposed to cells expressing the scrambled peptide. The FAK-derived sequence prevented this. These results suggest that blocking FAK-Akt1 interaction may prevent perioperative tumor dissemination and that analogs or mimics of this 7 amino acid FAK-derived peptide could impair metastasis.