Dugina Vera, Shagieva Galina, Khromova Natalya, Kopnin Pavel
a Belozersky Institute of Physico-Chemical Biology , Lomonosov Moscow State University , Moscow , Russia.
b Blokhin Russian Cancer Research Center , Moscow , Russia.
Cell Cycle. 2018;17(23):2610-2621. doi: 10.1080/15384101.2018.1553337. Epub 2018 Dec 5.
We have shown that cytoplasmic actin isoforms play different roles in neoplastic cell transformation. β-Cytoplasmic actin acts as a tumor suppressor, affecting epithelial differentiation, cell growth, cell invasion and tumor growth of colon and lung carcinoma cells. In contrast, γ-cytoplasmic actin enhances malignant features of tumor cells whose actin network regulation is carried out the γ-actin isoform. The goal of this study was to describe the role of cytoplasmic actins in cell cycle regulation of breast cancer cell lines MCF-7 and MDA-MB-231. The distinct roles of each cytoplasmic actin in the cell cycle driving were observed. β-Actin as well as γ-actin down-regulation inhibited proliferation of breast cancer cells, but only down-regulation of β-actin induced a significant decrease in diploid cell population and accumulation of tetraploid cells. Down-regulation of β-actin stimulated cyclin A2, B1 and D3 expression, whereas down-regulation of γ-actin reduced expression of these cyclins in both cell lines. Moreover, cyclin B1 and γ-actin were co-localized in mitotic control and β-actin-deficient cells. In mitotic MCF-7 cells down-regulation of β-actin caused an enrichment of prophase/metaphase population compared with control. γ-Actin down-regulation induced telophase enrichment. ERK1/2 and γ-actin co-localization and possible selective binding were revealed in MCF7 cells. β-Actin down-regulation induced ERK1/2 activation, while γ-actin down-regulation led to reduction of p-ERK1/2. A direct interaction of ERK1/2 with γ-actin and cyclin A2 in the same protein complex was also discovered. We suggest that γ-actin down-regulation leads to decrease of cyclin A2 level, inhibits ERK1/2 signaling and deceleration of breast cancer cells proliferation.
我们已经表明，细胞质肌动蛋白异构体在肿瘤细胞转化中发挥不同作用。β-细胞质肌动蛋白作为一种肿瘤抑制因子，影响结肠和肺癌细胞的上皮分化、细胞生长、细胞侵袭和肿瘤生长。相比之下，γ-细胞质肌动蛋白增强了肿瘤细胞的恶性特征，其肌动蛋白网络调节由γ-肌动蛋白异构体执行。本研究的目的是描述细胞质肌动蛋白在乳腺癌细胞系MCF-7和MDA-MB-231细胞周期调控中的作用。观察到每种细胞质肌动蛋白在细胞周期驱动中的不同作用。β-肌动蛋白以及γ-肌动蛋白的下调均抑制了乳腺癌细胞的增殖，但只有β-肌动蛋白的下调导致二倍体细胞群体显著减少和四倍体细胞积累。β-肌动蛋白的下调刺激了细胞周期蛋白A2、B1和D3的表达，而γ-肌动蛋白的下调降低了这两种细胞系中这些细胞周期蛋白的表达。此外，细胞周期蛋白B1和γ-肌动蛋白在有丝分裂控制和β-肌动蛋白缺陷细胞中共定位。在有丝分裂的MCF-7细胞中，与对照相比，β-肌动蛋白的下调导致前期/中期群体富集。γ-肌动蛋白的下调诱导末期富集。在MCF7细胞中发现了ERK1/2与γ-肌动蛋白的共定位以及可能的选择性结合。β-肌动蛋白的下调诱导ERK1/2激活，而γ-肌动蛋白的下调导致p-ERK1/2减少。还发现ERK1/2与γ-肌动蛋白和细胞周期蛋白A2在同一蛋白复合物中直接相互作用。我们认为，γ-肌动蛋白的下调导致细胞周期蛋白A2水平降低，抑制ERK1/2信号传导并减缓乳腺癌细胞增殖。
