Epithelial-mesenchymal transition of ovarian cancer cells is sustained by Rac1 through simultaneous activation of MEK1/2 and Src signaling pathways.
Epithelial-mesenchymal transition of ovarian cancer cells is sustained by Rac1 through simultaneous activation of MEK1/2 and Src signaling pathways.
复制标题
Rac 1通过同时激活MEK 1/2和Src信号通路维持卵巢癌细胞的上皮-间质转化。
作者：
Fang D;Chen H;Zhu JY;Wang W;Teng Y;Ding HF;Jing Q;Su SB;Huang S
上皮-间质转化（EMT）被认为是癌症进展的关键因素。多种因素已被确定为卵巢癌中有效的EMT诱导剂。然而，维持卵巢癌细胞EMT的分子机制仍不清楚。在这里，我们表明，SOS 1/EPS 8/ABI 1复合物的存在对于卵巢癌细胞的持续EMT特性至关重要。与SOS 1/EPS 8/ABI 1复合物作为Rac 1特异性鸟嘌呤核苷酸交换因子的作用一致，Rac 1的缺失导致间充质样卵巢癌细胞中大部分间充质性状的丧失，而表达组成型活性Rac 1导致上皮样卵巢癌细胞中的EMT。借助针对各种EMT相关信号通路的临床测试抑制剂，我们表明，只有MEK 1/2和Src抑制剂的联合治疗才能消除由间充质样卵巢癌细胞显示的组成型活性Rac 1主导的EMT和间充质性状。进一步的实验还表明，EMT可以诱导上皮样卵巢癌细胞的组成型活性MEK 1和Src，而不是单独表达。由于Erk和Src的活性在具有组成性活性Rac 1的卵巢癌细胞中更高，我们得出结论，Rac 1通过同时激活MEK 1/2和Src信号通路来维持卵巢癌细胞EMT。重要的是，我们证明了MEK 1/2和Src抑制剂的联合使用有效地抑制了腹膜内异种移植物的发展，并提高了卵巢癌荷瘤小鼠的存活率。这项研究表明，MEK 1/2和Src抑制剂的鸡尾酒代表了一种有效的治疗策略，对卵巢癌的进展。
Epithelial-mesenchymal transition (EMT) is regarded as a crucial contributing factor to cancer progression. Diverse factors have been identified as potent EMT inducers in ovarian cancer. However, molecular mechanism sustaining EMT of ovarian cancer cells remains elusive. Here, we show that the presence of SOS1/EPS8/ABI1 complex is critical for sustained EMT traits of ovarian cancer cells. Consistent with the role of SOS1/EPS8/ABI1 complex as a Rac1-specific guanine nucleotide exchange factor, depleting Rac1 results in the loss of most of mesenchymal traits in mesenchymal-like ovarian cancer cells while expressing constitutively active Rac1 leads to EMT in epithelial-like ovarian cancer cells. With the aid of clinically tested inhibitors targeting various EMT-associated signaling pathways, we show that only combined treatment of MEK1/2 and Src inhibitors can abolish constitutively active Rac1-led EMT and mesenchymal traits displayed by mesenchymal-like ovarian cancer cells. Further experiments also reveal that EMT can be induced in epithelial-like ovarian cancer cells by co-expressing constitutively active MEK1 and Src rather than either alone. As the activities of Erk and Src are higher in ovarian cancer cells with constitutively active Rac1, we conclude that Rac1 sustains ovarian cancer cell EMT through simultaneous activation of MEK1/2 and Src signaling pathways. Importantly, we demonstrate that combined use of MEK1/2 and Src inhibitors effectively suppresses development of intraperitoneal xenografts and prolongs the survival of ovarian cancer-bearing mice. This study suggests that cocktail of MEK1/2 and Src inhibitors represents an effective therapeutic strategy against ovarian cancer progression.