Targeting the E3 ubiquitin casitas B-lineage lymphoma decreases osteosarcoma cell growth and survival and reduces tumorigenesis.

Abstract

Targeting receptor tyrosine kinase (RTK) degradation may be an interesting approach to reduce RTK cell signaling in cancer cells. Here we show that increasing E3 ubiquitin ligase casitas B-lineage lymphoma (c-Cbl) expression using lentiviral infection decreased osteosarcoma cell replication and survival and reduced cell migration and invasion in murine and human osteosarcoma cells. Conversely, c-Cbl inhibition using short hairpin RNA (shRNA) increased osteosarcoma cell growth and survival, as well as invasion and migration, indicating that c-Cbl plays a critical role as a bone tumor suppressor. Importantly, the anticancer effect of increasing c-Cbl expression in osteosarcoma cells was related mainly to the downregulation of epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor alpha (PDGFRα). In a murine bone tumor model, increasing c-Cbl expression also reduced RTK expression, resulting in decreased tumor cell proliferation and survival and reduced tumor growth. Interestingly, increasing c-Cbl also markedly reduced lung metastasis in mice. Tissue microarray analysis revealed that low c-Cbl protein expression is associated with elevated EGFR and PDGFRα protein levels in human osteosarcoma with poor outcome. This study shows that increasing c-Cbl expression reduces osteosarcoma cell growth, survival, and metastasis in part through downregulation of RTKs, which supports the potential therapeutic interest of targeting c-Cbl in malignant bone diseases involving increased RTK.

• Authors: Nicolas Sévère, François-Xavier Dieudonné, Caroline Marty, Dominique Modrowski, Ana Patiño-García, Fernando Lecanda, Olivia Fromigué, Pierre J Marie
• Journal: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research (J Bone Miner Res) Vol. 27 Issue 10 Pg. 2108-17 (Oct 2012) ISSN: 1523-4681 [Electronic] United States
• PMID: 22623369 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 American Society for Bone and Mineral Research.

Chemical References

• Proto-Oncogene Proteins c-cbl
• Receptor Protein-Tyrosine Kinases

Topics

• Animals
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Cell Survival
• Cell Transformation, Neoplastic (pathology)
• Down-Regulation
• Female
• Gene Targeting
• Humans
• Lung Neoplasms (secondary)
• Mice
• Mice, Inbred BALB C
• Neoplasm Invasiveness
• Osteoblasts (enzymology, pathology)
• Osteosarcoma (enzymology, pathology)
• Proto-Oncogene Proteins c-cbl (metabolism)
• Receptor Protein-Tyrosine Kinases (metabolism)