Nuclear expression of ?-catenin promotes RB stability and resistance to TNF-induced apoptosis in colon cancer cells.

ABSTRACT: Tumor necrosis factor (TNF)-? 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 ?-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 ?-catenin exon-3 mutations in these two genetic backgrounds. TNF-induced apoptosis was also attenuated in human colon cancer cell lines with genetically activated ?-catenin. However, we found that HCT116 cells, which contain an activated allele of ?-catenin but do not express nuclear ?-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 ?-catenin and these cells could be sensitized to basal and/or TNF-induced apoptosis by the knockdown of ?-catenin or RB. In the apoptosis-resistant colon cancer cells, knockdown of ?-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 ?-catenin. Together, these results suggest that nuclear ?-catenin-dependent RB stabilization suppresses TNF-induced apoptosis in caspase-8-positive colon cancer cells.

SUBMITTER: Han J 

PROVIDER: S-EPMC4191841 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature