| First Author | Han J | Year | 2013 |
| Journal | Mol Cancer Res | Volume | 11 |
| Issue | 3 | Pages | 207-18 |
| PubMed ID | 23339186 | Mgi Jnum | J:205378 |
| Mgi Id | MGI:5544697 | Doi | 10.1158/1541-7786.MCR-12-0670 |
| Citation | Han J, et al. (2013) Nuclear expression of beta-catenin promotes RB stability and resistance to TNF-induced apoptosis in colon cancer cells. Mol Cancer Res 11(3):207-18 |
| abstractText | Tumor necrosis factor (TNF)-alpha 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 beta-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 beta-catenin exon-3 mutations in these two genetic backgrounds. TNF-induced apoptosis was also attenuated in human colon cancer cell lines with genetically activated beta-catenin. However, we found that HCT116 cells, which contain an activated allele of beta-catenin but do not express nuclear beta-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 beta-catenin and these cells could be sensitized to basal and/or TNF-induced apoptosis by the knockdown of beta-catenin or RB. In the apoptosis-resistant colon cancer cells, knockdown of beta-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 beta-catenin. Together, these results suggest that nuclear beta-catenin-dependent RB stabilization suppresses TNF-induced apoptosis in caspase-8-positive colon cancer cells. |
