Reduction of metastasis, cell invasion, and adhesion in mouse osteosarcoma by YM529/ONO-5920-induced blockade of the Ras/MEK/ERK and Ras/PI3K/Akt pathway

• Published in: Toxicology and applied pharmacology Vol. 259; no. 3; pp. 402 - 410
• Main Authors: Tsubaki, Masanobu, Satou, Takao, Itoh, Tatsuki, Imano, Motohiro, Ogaki, Mitsuhiko, Yanae, Masashi, Nishida, Shozo
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 15-03-2012; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; ADHESION; Akt; Animals; APOPTOSIS; Biological and medical sciences; Bisphosphonate; Cell Adhesion - drug effects; Cell Line, Tumor; Cell Movement - drug effects; CHILDREN; Diphosphonates - pharmacology; Diseases of the osteoarticular system; ERK; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Gene Expression Regulation, Neoplastic - drug effects; Imidazoles - pharmacology; Male; Matrix Metalloproteinases - genetics; Matrix Metalloproteinases - metabolism; Medical sciences; MESSENGER-RNA; METASTASES; MICE; Mice, Inbred C3H; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Neoplasm Invasiveness - prevention & control; Neoplasm Metastasis - prevention & control; OSTEOPOROSIS; Osteosarcoma; Osteosarcoma - drug therapy; Osteosarcoma - pathology; OSTEOSARCOMAS; PATIENTS; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; PROTEINS; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Ras; ras Proteins - antagonists & inhibitors; RNA, Messenger - metabolism; SERINE; SKELETON; THREONINE; Toxicology; TUMOR CELLS; Tumors of striated muscle and skeleton; ERK1/2; Bisphosphonate; PI3K; BPs; MEK1/2; Osteosarcoma; Ras; MMPs; Akt; ECM; ERK; Antiosteoporotic; Extracellular signal-regulated protein kinase; Diseases of the osteoarticular system; Diphosphonic acid derivatives; Minodronic acid; Metastasis; Bisphosphonates; Osteoarticular system; Reduction; Cell adhesion; Protooncogene; Sarcoma; Enzyme; Transferases; Rodentia; Akt protein kinase; Mitogen-activated protein kinase; Malignant tumor; Invasion; 1-Phosphatidylinositol 3-kinase; Vertebrata; Mammalia; Mouse; Animal; C-Onc gene; Bone; Ras gene; Cancer
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2012.01.024

Osteosarcoma is one of the most common primary malignant bone tumors in children and adolescents. Some patients continue to have a poor prognosis, because of the metastatic disease. YM529/ONO-5920 is a nitrogen-containing bisphosphonate that has been used for the treatment of osteoporosis. YM529/ONO-5920 has recently been reported to induce apoptosis in various tumors including osteosarcoma. However, the mode of metastasis suppression in osteosarcoma by YM529/ONO-5920 is unclear. In the present study, we investigated whether YM529/ONO-5920 inhibited tumor cell migration, invasion, adhesion, or metastasis in the LM8 mouse osteosarcoma cell line. We found that YM529/ONO-5920 significantly inhibited metastasis, cell migration, invasion, and adhesion at concentrations that did not have antiproliferative effects on LM8 cells. YM529/ONO-5920 also inhibited the mRNA expression and protein activities of matrix metalloproteinases (MMPs). In addition, YM529/ONO-5920 suppressed phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and the serine/threonine protein kinase B (Akt) by the inhibition of Ras prenylation. Moreover, U0126, a mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, and LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, also inhibited LM8 cell migration, invasion, adhesion, and metastasis, as well as the mRNA expression and protein activities of MMP-1, MMP-2, MMP-9, and MT1-MMP. The results indicated that YM529/ONO-5920 suppressed the Ras/MEK/ERK and Ras/PI3K/Akt pathways, thereby inhibiting LM8 cell migration, invasion, adhesion, and metastasis. These findings suggest that YM529/ONO-5920 has potential clinical applications for the treatment of tumor cell metastasis in osteosarcoma.
► We investigated whether YM529/ONO-5920 inhibited tumor metastasis in osteosarcoma. ► YM529/ONO-5920 inhibited metastasis, cell migration, invasion, and adhesion. ► YM529/ONO-5920 suppressed Ras signalings. ► YM529/ONO-5920 has potential clinical applications for the treatment in osteosarcoma.