title: 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.affiliation: Laboratory of Osteoblast Biology and Pathology, INSERM U606, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sévère
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Dieudonné
authors.forename: Caroline
authors.initials: C
authors.lastname: Marty
authors.forename: Dominique
authors.initials: D
authors.lastname: Modrowski
authors.forename: Ana
authors.initials: A
authors.lastname: Patiño-García
authors.forename: Fernando
authors.initials: F
authors.lastname: Lecanda
authors.forename: Olivia
authors.initials: O
authors.lastname: Fromigué
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Marie
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D015536:Down-Regulation; D005260:Female; D018390:Gene Targeting; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D010006:Osteoblasts / Q000201:enzymology / Q000473:pathology; D012516:Osteosarcoma / Q000201:enzymology* / Q000473:pathology*; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism
chemical_list: D050721:Proto-Oncogene Proteins c-cbl; D020794:Receptor Protein-Tyrosine Kinases