Suppressed invasive and migratory behaviors of SW1353 chondrosarcoma cells through the regulation of Src, Rac1 GTPase, and MMP13.
Suppressed invasive and migratory behaviors of SW1353 chondrosarcoma cells through the regulation of Src, Rac1 GTPase, and MMP13.
复制标题
通过调节 Src、Rac1 GTPase 和 MMP13 抑制 SW1353 软骨肉瘤细胞的侵袭和迁移行为。
DOI：
10.1016/j.cellsig.2015.08.014
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发表时间：
2015
影响因子：
4.8
通讯作者：
Hamamura,Kazunori
中科院分区：
文献类型：
--
作者：
Xu,Wenxiao;Wan,Qiaoqiao;Na,Sungsoo;Yokota,Hiroki;Yan,Jing-Long;Hamamura,Kazunori
软骨肉瘤是第二种常见的原发性骨癌。作为对内质网应激的反应，eIF2α介导的信号被激活以诱导细胞凋亡。然而，其对软骨肉瘤侵袭和迁移行为的影响尚不清楚。着眼于src激酶、rac1GTP酶和MMP13的潜在作用，我们研究了eIF2α对SW1353软骨肉瘤细胞的调控作用。特别是，我们使用了两种化学试剂(salubrina，Sal；和guanabenz，Gu)来提高eIF2α的磷酸化水平。结果表明，丹参和谷氨酸均能剂量依赖性地降低SW1353软骨肉瘤细胞的侵袭力和运动能力。应用荧光共振能量转移(FRET)技术的实时成像显示，Sal和Gu以eIF2α依赖的方式下调Src激酶和rac1GTP酶的活性。RNAi实验支持eIF2α介导的调控网络对Sal和Gu的抑制作用。部分沉默MMP13也抑制了SW1353软骨肉瘤细胞的恶性表型。然而，由于给予SAL而不是Gu降低了MMP13的表达，因此MMP13不受eIF2α的调节。综上所述，我们证明了eIF2α依赖和独立的途径调节了软骨肉瘤细胞的侵袭和运动，SAL对src、rac1和MMP13的失活可能为抗转移软骨肉瘤细胞提供一种潜在的辅助治疗方法。
Chondrosarcoma is the second frequent type of primary bone cancer. In response to stress to the endoplasmic reticulum, activation of eIF2α-mediated signaling is reported to induce apoptosis. However, its effects on invasive and migratory behaviors of chondrosarcoma have not been understood. Focusing on potential roles of Src kinase, Rac1 GTPase, and MMP13, we investigated eIF2α-driven regulation of SW1353 chondrosarcoma cells. In particular, we employed two chemical agents (salubrinal, Sal; and guanabenz, Gu) that elevate the level of eIF2α phosphorylation. The result revealed that both Sal and Gu reduced invasion and motility of SW1353 chondrosarcoma cells in a dose dependent manner. Live imaging using a fluorescent resonance energy transfer (FRET) technique showed that Sal and Gu downregulated activities of Src kinase as well as Rac1 GTPase in an eIF2α dependent manner. RNA interference experiments supported an eIF2α-mediated regulatory network in the inhibitory role of Sal and Gu. Partial silencing of MMP13 also suppressed malignant phenotypes of SW1353 chondrosarcoma cells. However, MMP13 was not regulated via eIF2α since administration of Sal but not Gu reduced expression of MMP13. In summary, we demonstrate that eIF2α dependent and independent pathways regulate invasion and motility of SW1353 chondrosarcoma cells, and inactivation of Src, Rac1, and MMP13 by Sal could provide a potential adjuvant therapy for combating metastatic chondrosarcoma cells.