Unravelling new oncogenic functions of IKKα : towards a better understanding of colorectal carcinogenesis
Numerous studies have shown that the protein kinase IKKα is associated with cancer progression and metastasis in different models. However, the mechanisms underlying IKKα tumorigenic functions are poorly understood. We have here demonstrated that intestinal-specific deletion of IKKα does not affect...
| Autor: | |
|---|---|
| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2017 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/664812 |
| Acceso en línea: | http://hdl.handle.net/10803/664812 |
| Access Level: | acceso abierto |
| Palabra clave: | IKKα BRAF Colorectal cancer DNA damage Therapy Càncer colorectal Dany a l'ADN Teràpia 616.3 |
| Sumario: | Numerous studies have shown that the protein kinase IKKα is associated with cancer progression and metastasis in different models. However, the mechanisms underlying IKKα tumorigenic functions are poorly understood. We have here demonstrated that intestinal-specific deletion of IKKα does not affect intestinal homeostasis but greatly decreases tumour formation in the ApcMin/+ background associated with reduced stemness and proliferation. In advanced human colorectal cancer (CRC), we identified a new oncogenic form of IKKα (p45-IKKα) that sustains CRC cell survival downstream of BRAF. We have here shown that IKKα regulates phosphorylation of the DNA damage repair proteins 53BP1 and KAP1 thus facilitating DNA repair in CRC cells after genotoxic stress. Finally, we used patient-derived tumouroids and orthotopic xenograft models to demonstrate the possibility of using BRAF or IKKα inhibitors to enhance the effect of DNA damage-based therapies on CRC. |
|---|