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.

Abstract

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.

• Authors: Masanobu Tsubaki, Takao Satou, Tatsuki Itoh, Motohiro Imano, Mitsuhiko Ogaki, Masashi Yanae, Shozo Nishida
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 259 Issue 3 Pg. 402-10 (Mar 15 2012) ISSN: 1096-0333 [Electronic] United States
• PMID: 22326785 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Diphosphonates
• Imidazoles
• Phosphoinositide-3 Kinase Inhibitors
• RNA, Messenger
• YM 529
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases
• Mitogen-Activated Protein Kinase Kinases
• Matrix Metalloproteinases
• ras Proteins

Topics

• Animals
• Cell Adhesion (drug effects)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Diphosphonates (pharmacology)
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors)
• Gene Expression Regulation, Neoplastic (drug effects)
• Imidazoles (pharmacology)
• Male
• Matrix Metalloproteinases (genetics, metabolism)
• Mice
• Mice, Inbred C3H
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors)
• Neoplasm Invasiveness (prevention & control)
• Neoplasm Metastasis (prevention & control)
• Osteosarcoma (drug therapy, pathology)
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• RNA, Messenger (metabolism)
• ras Proteins (antagonists & inhibitors)