title: Sorafenib induces growth inhibition and apoptosis in human synovial sarcoma cells via inhibiting the RAF/MEK/ERK signaling pathway.
abstract: Synovial sarcoma is a soft tissue sarcoma with poor prognosis and lack of response to conventional cytotoxic chemotherapy. The regulatory mechanisms for the rapid proliferation of synovial sarcoma cells and the particular aggressiveness of this sarcoma remain poorly understood. Mitogen-activated protein kinase (MAPK) cascades have been shown to play important roles in synovial sarcoma survival. Sorafenib (Nexavar, BAY 43-9006), a potent recombinant activated factor (RAF) inhibitor, inhibits the MAPK signaling pathway both in vitro and in vivo. In this study, we examined the inhibitory proliferation effects of sorafenib in synovial sarcoma growth and evaluated whether sorafenib modulates MAPK and tumor apoptosis cascades in human synovial sarcoma cell lines SW982 and HS-SY-II. Our results indicated that sorafenib effectively inhibited cellular proliferation and induces apoptosis of these two cells. Sorafenib inhibited the phosphorylation of MEK and ERK, downregulated cyclin D1 and Rb levels, caused G(1) arrest and S phase decrease, and induced apoptosis as confirmed by flow cytometry and the TUNEL assay. Furthermore, Bcl-xl and Mcl-1 levels significantly decreased, whereas expression levels of the proteins bcl-2 and bax were unchanged in response to sorafenib treatment in SW982 and HS-SY-II cells. In conclusion, our findings demonstrate that sorafenib is effective for growth inhibition of synovial sarcoma cell lines in vitro and suggest that sorafenib may be a new therapeutic option for patients with synovial sarcoma.
authors.affiliation: Musculoskeletal Tumor Center, Peking University Peoples' Hospital, Beijing, China.
authors.forename: Chang-Liang
authors.initials: CL
authors.lastname: Peng
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.forename: Tao
authors.initials: T
authors.lastname: Ji
authors.forename: Tingting
authors.initials: T
authors.lastname: Ren
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.forename: Da-Sen
authors.initials: DS
authors.lastname: Li
authors.forename: Hua-Yi
authors.initials: HY
authors.lastname: Qu
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
authors.forename: Shun
authors.initials: S
authors.lastname: Tang
authors.forename: Tai-Qiang
authors.initials: TQ
authors.lastname: Yan
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Tang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001557:Benzenesulfonates / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019938:Cyclin D1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D013584:Sarcoma, Synovial / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D000077157:Sorafenib; D051020:bcl-X Protein / Q000378:metabolism; D048490:raf Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D001557:Benzenesulfonates; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010671:Phenylurea Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D016160:Retinoblastoma Protein; D051020:bcl-X Protein; D019938:Cyclin D1; D009536:Niacinamide; D000077157:Sorafenib; D017346:Protein Serine-Threonine Kinases; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases