Endothelin-1 Promotes Osteosarcoma Cell Invasion and Survival against Cisplatin-induced Apoptosis

• Published in: Clinical orthopaedics and related research Vol. 469; no. 11; pp. 3190 - 3199
• Main Authors: Zhao, Yuanting, Liao, Qiande, Zhu, Yong, Long, Haitao
• Format: Journal Article
• Language: English
• Published: New York Springer-Verlag 01.11.2011; Springer; Lippincott Williams & Wilkins Ovid Technologies
• Subjects: Adolescent; Adult; Antagonists; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Basic Research; Biological and medical sciences; Bone matrix; Bone Neoplasms - drug therapy; Bone Neoplasms - genetics; Bone Neoplasms - metabolism; Bone remodelling; Cell migration; Cell number; Cell proliferation; Cell survival; Cell Survival - drug effects; Child; Child, Preschool; Cisplatin; Cisplatin - pharmacology; Conservative Orthopedics; Diseases of the osteoarticular system; Drug Screening Assays, Antitumor; Endothelin 1; Endothelin A Receptor Antagonists; Endothelin ETB receptors; Endothelin-1 - genetics; Endothelin-1 - metabolism; Enzyme-linked immunosorbent assay; Female; Gene Expression; Humans; Male; Malignancy; Medical sciences; Medicine; Medicine & Public Health; Metastases; Middle Aged; mRNA; Neoplasm Invasiveness; Neoplasm Staging; Orthopedics; Osteosarcoma; Osteosarcoma - drug therapy; Osteosarcoma - genetics; Osteosarcoma - metabolism; Osteosarcoma cells; Polymerase chain reaction; Receptor, Endothelin A - genetics; Receptor, Endothelin A - metabolism; RNA, Messenger - metabolism; RNA, Neoplasm - analysis; Sports Medicine; Surgery; Surgical Orthopedics; Tumor; Tumor Cells, Cultured; Tumors of striated muscle and skeleton; Young Adult; Cell Invasion Ability; BQ123; Apoptotic Stress; Cell Death Rate; Antineoplastic agent; Prognosis; Sarcoma; Diseases of the osteoarticular system; Endothelin 1; Malignant tumor; Survival; Cisplatin; Invasion; Alkylating agent; Osteosarcoma; Orthopedics; Bone; Cancer; Platinum II Complexes; Apoptosis
• ISSN: 0009-921X; 1528-1132; 1528-1132
• DOI: 10.1007/s11999-011-1939-2

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. Question/purposes 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. Clinical Relevance 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.