IKKβ-Mediated Resistance to Skin Cancer Development Is Ink4a/Arf- Dependent

• Published in: Molecular cancer research Vol. 15; no. 9; pp. 1255 - 1264
• Main Authors: Page, Angustias, Bravo, Ana, Suarez-Cabrera, Cristian, Alameda, Josefa P, Casanova, M Llanos, Lorz, Corina, Segrelles, Carmen, Segovia, José C, Paramio, Jesús M, Navarro, Manuel, Ramirez, Angel
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.09.2017
• Subjects: Animal models; Animals; Cancer; Carcinogenesis; Carcinogens; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; Cyclin-dependent kinase inhibitors; Epigenesis, Genetic; I-kappa B Kinase - biosynthesis; I-kappa B Kinase - genetics; INK4 protein; Intestine; Kinases; Lungs; Mice; Mice, Transgenic; Mutation; NF-κB protein; p53 Protein; Protein kinase; Proteins; Proteomics; Signaling; Skin cancer; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Skin resistance; Squamous cell carcinoma; Tumor suppressor genes; Tumor Suppressor Protein p14ARF - genetics; Tumor Suppressor Protein p14ARF - metabolism; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-17-0157

IKKβ (encoded by ) is a protein kinase that regulates the activity of numerous proteins important in several signaling pathways, such as the NF-κB pathway. IKKβ exerts a protumorigenic role in several animal models of lung, hepatic, intestinal, and oral cancer. In addition, genomic and proteomic studies of human tumors also indicate that gene is amplified or overexpressed in multiple tumor types. Here, the relevance of IKKβ in skin cancer was determined by performing carcinogenesis studies in animal models overexpressing IKKβ in the basal skin layer. IKKβ overexpression resulted in a striking resistance to skin cancer development and an increased expression of several tumor suppressor proteins, such as p53, p16, and p19. Mechanistically, this skin tumor-protective role of IKKβ is independent of p53, but dependent on the activity of the locus. Interestingly, in the absence of p16 and p19, IKKβ-increased expression favors the appearance of cutaneous spindle cell-like squamous cell carcinomas, which are highly aggressive tumors. These results reveal that IKKβ activity prevents skin tumor development, and shed light on the complex nature of IKKβ effects on cancer progression, as IKKβ can both promote and prevent carcinogenesis depending on the cell type or molecular context. The ability of IKKβ to promote or prevent carcinogenesis suggests the need for further evaluation when targeting this protein. .