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

Jinbo Han, Rossana C. Soletti, Anil Sadarangani, Priya Sridevi, Michael E. Ramirez, Lars Eckmann, Helena L. Borges, Jean Y.J. Wang

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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 inflammationassociated 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 TNFinduced 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 apoptosisresistant 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,RBre-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.

Original languageEnglish
Pages (from-to)207-218
Number of pages12
JournalMolecular Cancer Research
Volume11
Issue number3
DOIs
StatePublished - Mar 2013
Externally publishedYes

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