title: Endothelin-1 promotes osteosarcoma cell invasion and survival against cisplatin-induced apoptosis.
abstract: BACKGROUND
  Endothelin-1 (ET-1) participates in a wide range of cancer-relevant processes including cell proliferation, inhibition of apoptosis, matrix remodeling, bone deposition, and metastases. Although ET-1 reportedly promotes osteosarcoma (OS) cell invasion, suggesting an important role of ET-1 in OS metastasis, the role of ET-1 in OS remains unclear.
  
  
  OBJECTIVE
  We asked whether (1) ET-1 expression is associated with the malignancy of OS, (2) ET-1 enhances the cell invasion ability of OS, and (3) ET-1 promotes OS cell survival against apoptotic stress.
  
  
  METHODS
  We cultured primary OS specimens from 22 patients with Stages II (OS-II) and III (OS-III) in real-time quantitative RT-PCR and ELISA to compare ET-1 expression. We used Transwell(®) cell invasion assays (in triplicate) to assess the invasion ability of cells in the presence or absence of exogenous ET-1 and/or ET receptor antagonists. We compared cell apoptosis rate among the cells treated with cisplatin in the presence or absence of exogenous ET-1 and/or ET receptor antagonists. We used OS cell line MG-63 in all experiments as a reference.
  
  
  RESULTS
  Real-time quantitative RT-PCR and ELISA showed OS-III cells had greater ET-1 expression than OS-II cells at the mRNA and the secreted protein levels. Transwell(®) cell invasion assays showed OS-III cells had a greater migrated cell number than OS-II cells, which could be abrogated by ET(A) receptor antagonist BQ123 (100 pmol/L), but not ET(B) receptor antagonist BQ788 (1 μmol/L); exogenous ET-1 dose-dependently promoted OS cell migration, which could be inhibited by BQ123 (100 pmol/L). Cisplatin (10 nmol/L) induced less apoptosis in OS-III cells than in OS-II cells; exogenous ET-1 dose-dependently promoted OS cell survival against cisplatin-induced apoptosis; both effects were reversed by BQ123 (1 μmol/L), but not BQ788 (1 μmol/L).
  
  
  CONCLUSIONS
  Increased ET-1 expression appears to be associated with increased malignancy of OS. ET-1 promotes OS cell invasion and survival against cisplatin-induced apoptosis through the ET(A) receptor.
  
  
  CONCLUSIONS
  The ET-1/ET(A) pathway may represent an important target for treating OS, because blocking the ET(A) receptor with a selective antagonist can inhibit OS cell invasion and potentiate a chemotherapeutic agent's effect on OS.
authors.affiliation: Department of Orthopedics, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan 410078, People's Republic of China.
authors.forename: Yuanting
authors.initials: Y
authors.lastname: Zhao
authors.forename: Qiande
authors.initials: Q
authors.lastname: Liao
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhu
authors.forename: Haitao
authors.initials: H
authors.lastname: Long
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000032:analysis; D044022:Receptor, Endothelin A / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D044022:Receptor, Endothelin A; D002945:Cisplatin