E3 ubiquitin-protein ligase CBL inhibits non-small cell lung cancer progression via ubiquitination and degradation of KDR
Abstract Background Non-small cell lung cancer (NSCLC) is the predominant type of lung cancer and continues to be a major cause of cancer-related death globally. The identification of novel molecular targets is essential for developing effective therapeutic strategies. Methods In this study, we inve...
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| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-06-01
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| Series: | Cell Division |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13008-025-00159-9 |
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| Summary: | Abstract Background Non-small cell lung cancer (NSCLC) is the predominant type of lung cancer and continues to be a major cause of cancer-related death globally. The identification of novel molecular targets is essential for developing effective therapeutic strategies. Methods In this study, we investigated the functional and mechanistic role of the E3 ubiquitin-protein ligase CBL in NSCLC progression. CBL expression was analyzed in NSCLC tumor tissues and cell lines using quantitative RT-PCR and Western blotting. The impact of CBL on NSCLC cell proliferation, migration, and invasion was assessed by a number of in vitro functional tests. Co-immunoprecipitation (Co-IP) and ubiquitination assays were performed to elucidate the molecular interaction between CBL and kinase insert domain receptor (KDR), a key mediator of angiogenesis. Results CBL expression was markedly reduced in NSCLC tissues and cell lines relative to normal equivalents. Gain- and loss-of-function tests demonstrated that CBL suppressed the NSCLC cell proliferation, migration, and invasion, highlighting its tumor-suppressive role. Mechanistically, CBL regulates KDR protein degradation via ubiquitination, thereby disrupting KDR-mediated signaling pathways associated with angiogenesis and tumor progression. Notably, overexpression of KDR reversed the anti-tumor effects of CBL, restoring the aggressive phenotype of NSCLC cells. These results suggest that CBL acts as a negative regulator of NSCLC malignancy through targeted degradation of KDR. Conclusion Our findings identify CBL as a functional tumor suppressor in NSCLC that exerts its anti-cancer effects via ubiquitin-mediated degradation of KDR. The CBL-KDR axis signifies a new regulatory route with significant therapeutic potential for NSCLC therapy. |
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| ISSN: | 1747-1028 |