Suppressed Invasive And Migratory Behaviors Of 5w1353 Chondro Sarcoma Cells Through The Regulation Of Src, Rac1 Gtpase, And Mmp13

Chondrosarcoma is the second frequent type of primary bone cancer. In response to stress to the endoplasmic reticulum, activation of eIF2 alpha-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 eIF2 alpha-driven regulation of SW1353 chondrosarcoma cells. In particular, we employed two chemical agents (salubrinal, Sal; and guanabenz, Gu) that elevate the level of eIF2 alpha 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 Sit kinase as well as Rac1 GTPase in an eIF2 alpha dependent manner. RNA interference experiments supported an eIF2 alpha-mediated regulatory network in the inhibitory role of Sal and Gu. Partial silencing of MMP13 also suppressed malignant phenotypes of 5W1353 chondrosarcoma cells. However, MMP13 was not regulated via eIF2 alpha since administration of Sal but not Gu reduced expression of MMP13. In summary, we demonstrate that eIF2a 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. (C) 2015 Elsevier Inc. All rights reserved.