title: Nuclear expression of β-catenin promotes RB stability and resistance to TNF-induced apoptosis in colon cancer cells.
abstract: 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.
authors: Moores UCSD Cancer Center, University of California San Diego, La Jolla, California 92093, USA.
authors: Jinbo
authors: J
authors: Han
authors: Rossana C
authors: RC
authors: Soletti
authors: Anil
authors: A
authors: Sadarangani
authors: Priya
authors: P
authors: Sridevi
authors: Michael E
authors: ME
authors: Ramirez
authors: Lars
authors: L
authors: Eckmann
authors: Helena L
authors: HL
authors: Borges
authors: Jean Y J
authors: JY
authors: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D053181:Caspase 8 / Q000378:metabolism; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: D016160:Retinoblastoma Protein; D014409:Tumor Necrosis Factor-alpha; D051176:beta Catenin; D053181:Caspase 8