thiourea and Chondrosarcoma

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.

Topics: Bone Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chondrosarcoma; Cinnamates; Eukaryotic Initiation Factor-2; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Guanabenz; Humans; Matrix Metalloproteinase 13; Neoplasm Invasiveness; rac1 GTP-Binding Protein; src-Family Kinases; Thiourea; Tumor Necrosis Factor-alpha

Chondrosarcoma is a common soft tissue malignancy. Although radiation induces DNA damage and integrated stress response (ISR), the sensitivity to ionizing radiation differs among tissues, and traditional radiotherapy for chondrosarcoma is not deemed effective. We examined whether administration of an ISR-inducing agent enhances radiosensitivity of chondrosarcoma.. SW1353 chondrosarcoma cells and C28/I2 chondrocytes were irradiated with 1-10 Gy of X-rays and cultured with 1-20 μM salubrinal, which is known to induce ISR through inhibiting dephosphorylation of eukaryotic translation initiation factor 2α (eIF2α).. The numbers of cells were reduced after irradiation, and salubrinal further reduced them as well as their clonogenic survival. The levels of phosphorylated eIF2α were elevated by irradiation and administration of salubrinal. SW1353 cells treated with salubrinal after irradiation were more sensitive to radiation than those treated with salubrinal prior to irradiation.. Salubrinal may serve as a potential chemotherapeutic agent for enhancing radiosensitivity, and its efficacy may depend upon the dose used and the timing of its administration.

Topics: Cell Death; Cell Line, Tumor; Chondrosarcoma; Cinnamates; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Eukaryotic Initiation Factor-2; Humans; Neoplastic Stem Cells; Phosphorylation; Radiation-Sensitizing Agents; Thiourea