title: Suppressed invasive and migratory behaviors of SW1353 chondrosarcoma cells through the regulation of Src, Rac1 GTPase, and MMP13.
abstract: 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.
authors: Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA; Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China.
authors: Wenxiao
authors: W
authors: Xu
authors: Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA.
authors: Qiaoqiao
authors: Q
authors: Wan
authors: Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA.
authors: Sungsoo
authors: S
authors: Na
authors: Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202 USA.
authors: Hiroki
authors: H
authors: Yokota
authors: Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China. Electronic address: hamak@dpc.agu.ac.jp.
authors: Jing-Long
authors: JL
authors: Yan
authors: Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA; Department of Pharmacology, School of Dentistry, Aichi-Gakuin University, Nagoya 464-8650, Japan. Electronic address: yjl_8899@163.com.
authors: Kazunori
authors: K
authors: Hamamura
mesh_terms: D001859:Bone Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002813:Chondrosarcoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D002934:Cinnamates / Q000494:pharmacology; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006143:Guanabenz / Q000494:pharmacology; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D002934:Cinnamates; D015852:Eukaryotic Initiation Factor-2; C107953:RAC1 protein, human; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; C496827:salubrinal; D019061:src-Family Kinases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020830:rac1 GTP-Binding Protein; D006143:Guanabenz; D013890:Thiourea
keywords: Chondrosarcoma; MMP13; Rac1; Src; eIF2α