Nuclear Expression of β-Catenin Promotes RB Stability and Resistance to TNF-Induced Apoptosis in Colon Cancer Cells
| Autor: | Anil Sadarangani, Priya Sridevi, Rossana C. Soletti, Lars Eckmann, Jean Y. J. Wang, Jinbo Han, Michael E. Ramirez, Helena L. Borges |
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| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
Apoptosis Caspase 8 Retinoblastoma Protein Article Mice Cyclin D1 medicine Animals Humans Molecular Biology beta Catenin Cell Nucleus biology Tumor Necrosis Factor-alpha Retinoblastoma protein HCT116 Cells Molecular biology Gene Expression Regulation Neoplastic Cell nucleus medicine.anatomical_structure Oncology Cell culture Gene Knockdown Techniques Colonic Neoplasms biology.protein Cancer research Tumor necrosis factor alpha Signal transduction Signal Transduction |
| Zdroj: | Molecular Cancer Research. 11:207-218 |
| ISSN: | 1557-3125 1541-7786 |
| DOI: | 10.1158/1541-7786.mcr-12-0670 |
| Popis: | Tumor necrosis factor (TNF)-α promotes tumor development under chronic inflammation. Because TNF also activates caspase-8, selective inhibition of TNF-induced extrinsic apoptosis would be required for inflammation-associated tumor growth. In a mouse model of inflammation-associated colon carcinogenesis, we found nuclear expression of β-catenin in tumors of wild-type, but not mutant, mice that were made resistant to TNF-induced apoptosis by a germline mutation blocking caspase cleavage of the retinoblastoma (RB) protein, despite similar frequencies of β-catenin exon-3 mutations in these two genetic backgrounds. TNF-induced apoptosis was also attenuated in human colon cancer cell lines with genetically activated β-catenin. However, we found that HCT116 cells, which contain an activated allele of β-catenin but do not express nuclear β-catenin, were sensitive to TNF-induced apoptosis. In HCT116 cells, TNF stimulated efficient RB cleavage that preceded chromatin condensation. In contrast, TNF did not induce RB cleavage in colon cancer cells expressing nuclear β-catenin and these cells could be sensitized to basal and/or TNF-induced apoptosis by the knockdown of β-catenin or RB. In the apoptosis-resistant colon cancer cells, knockdown of β-catenin led to a reduction in the RB protein without affecting RB mRNA. Furthermore, ectopic expression of the caspase-resistant, but not the wild-type, RB re-established resistance to TNF-induced caspase activation in colon cancer cells without β-catenin. Together, these results suggest that nuclear β-catenin–dependent RB stabilization suppresses TNF-induced apoptosis in caspase-8–positive colon cancer cells. Visual Overview: http://mcr.aacrjournals.org/content/11/3/207/F1.large.jpg. Mol Cancer Res; 11(3); 207–18. ©2012 AACR. |
| Databáze: | OpenAIRE |
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