An E3 ubiquitin ligase: C-Cbl: A new therapeutic target of lung cancer

Background: Casitas B-lineage lymphoma (Cbl) is an E3 ubiquitin ligase of many tyrosine kinase receptors. The authors previously detected c-Cbl mutation and low protein expression in non-small cell lung cancer (NSCLC). Therefore, it was hypothesized that overexpression of wild-type c-Cbl (c-Cbl WT) exhibits tumor growth inhibition. METHODS: Wound healing and transwell assays were conducted to examine cell motility after c-Cbl WT transfection in NSCLC cell lines. The cell cycle was investigated by flow cytometry. A549 and H1299-Luc c-Cbl WT-transfected xenografts and experimental metastasis models were performed to investigate tumor growth and metastasis inhibition in vivo. RESULTS: Wound healing and transwell assays demonstrated inhibition of migration in the A549 and H226br cells 4 to 24 hours after transfection. Ectopic c-Cbl WT expression was found to reduce cell proliferation at 48 hours in A549 cells. It is important to note that A549 and H1299-Luc cells with ectopic c-Cbl WT expression demonstrated inhibition of tumor growth in vivo. A549 cells overexpressing c-Cbl WT inhibited tumor metastasis in animal models. CONCLUSIONS: To the best of the authors' knowledge, the current study is the first to demonstrate that c-Cbl WT protein overexpression inhibits tumor metastasis and tumor growth in lung cancer xenograft models. These results provide evidence that ectopic expression of c-Cbl WT protein can be potentially applied as targeted therapy for the treatment of lung cancer.