Zeng Bixi, Devadoss Dinesh, Wang Shouye, Vomhof-DeKrey Emilie E, Kuhn Leslie A, Basson Marc D
Department of Surgery, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota, United States.
Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota, United States.
Oncotarget. 2017 Aug 24;8(58):98051-98067. doi: 10.18632/oncotarget.20556. eCollection 2017 Nov 17.
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.
手术环境或循环系统中的力通过需要FAK-Akt1相互作用的信号传导激活癌细胞粘附并增强转移。阻碍FAK-Akt1相互作用可能会抑制围手术期肿瘤播散，促进根治性癌症手术，而不会产生全身性FAK或AKT抑制剂毒性。对FAK进行系列截短和结构设计突变体鉴定出FAK内一个七氨基酸的短螺旋结构，该结构能有效竞争Akt1-FAK相互作用。在短暂暴露于15mmHg升高压力（类似于腹腔镜手术或术后压力）的人SW620结肠癌细胞中，这种源自FAK的肽的腺病毒过表达抑制了压力诱导的FAK磷酸化和AKT-FAK共免疫沉淀。腺病毒来源的FAK肽表达不仅阻止了SW620对胶原蛋白-I包被平板的粘附激活，也阻止了其对小鼠手术伤口的粘附激活。而乱序肽则没有这种作用。最后，我们通过在冲洗和缝合前让癌细胞短暂粘附于小鼠手术伤口来模拟手术中肿瘤细胞的脱落。在15mmHg升高压力下对SW620细胞进行30分钟预孵育，会损害随后暴露于表达乱序肽细胞的小鼠的无瘤生存期。而源自FAK的序列可防止这种情况。这些结果表明，阻断FAK-Akt1相互作用可能会防止围手术期肿瘤播散，并且这种7氨基酸FAK衍生肽的类似物或模拟物可能会损害转移。
