Kallergi Galatea, Agelaki Sofia, Markomanolaki Harris, Georgoulias Vassilis, Stournaras Christos
Department of Biochemistry, University of Crete Medical School and University Hospital, Heraklion, Greece.
Cell Physiol Biochem. 2007;20(6):977-86. doi: 10.1159/000110458.
We have recently identified a specific signaling pathway that regulates actin reorganization in malignant human breast and prostate epithelial cells associated with FAK, PI-3K and Rac1 activation. Here we report that this pathway operates in MCF7 cells upon activation of membrane androgen receptors (mAR). Stimulation of mAR by the non-permeable testosterone-BSA conjugate resulted in early actin reorganization documented by quantitative measurements of actin dynamics and morphological analysis of microfilament organization. This effect was regulated by early phosphorylation of FAK and subsequent PI-3K and Rac1 activation. The functional role of this pathway was further shown in A375 melanoma cells. Treatment with the opioid antagonist alpha(s1) casomorphin resulted in rapid and potent actin remodeling in A375 cells, regulated by rapid activation of the FAK/PI-3K/Rac1 signaling. Pretreatment of both cell lines with the specific PI-3K inhibitor wortmannin blocked actin reorganization. Interestingly, wound healing assays revealed that testosterone-BSA and alpha (s1) casomorphin significantly inhibited MCF7 and A375 cell motility respectively. These effects were abrogated through blockade of PI-3K signaling by wortmannin. The results presented here indicate that actin reorganization through FAK/PI3-K/Rac-1 activation operates in various human cancer cell systems supporting a functional role for FAK/PI-3K/Rac1/actin signaling in controlling cell motility.
我们最近发现了一条特定的信号通路，该通路在与黏着斑激酶（FAK）、磷脂酰肌醇-3激酶（PI-3K）和Rac1激活相关的恶性人乳腺和前列腺上皮细胞中调节肌动蛋白重组。在此我们报告，这条通路在膜雄激素受体（mAR）激活后在MCF7细胞中发挥作用。不可渗透的睾酮-牛血清白蛋白（testosterone-BSA）偶联物对mAR的刺激导致了早期肌动蛋白重组，这通过对肌动蛋白动力学的定量测量和微丝组织的形态学分析得以记录。这种效应受FAK的早期磷酸化以及随后的PI-3K和Rac1激活的调节。这条通路的功能作用在A375黑色素瘤细胞中得到了进一步证实。用阿片样物质拮抗剂α(s1)酪蛋白吗啡（alpha(s1) casomorphin）处理导致A375细胞中快速且有力的肌动蛋白重塑，这受FAK/PI-3K/Rac1信号的快速激活调节。用特异性PI-3K抑制剂渥曼青霉素（wortmannin）对这两种细胞系进行预处理可阻断肌动蛋白重组。有趣的是，伤口愈合试验显示，睾酮-BSA和α(s1)酪蛋白吗啡分别显著抑制MCF7和A375细胞的迁移。渥曼青霉素阻断PI-3K信号后，这些效应被消除。此处呈现的结果表明，通过FAK/PI3-K/Rac-1激活进行的肌动蛋白重组在多种人类癌细胞系统中发挥作用，支持FAK/PI-3K/Rac1/肌动蛋白信号在控制细胞迁移方面的功能作用。
