| First Author | Han J | Year | 2013 |
| Journal | Mol Biol Cell | Volume | 24 |
| Issue | 4 | Pages | 465-73 |
| PubMed ID | 23264463 | Mgi Jnum | J:200225 |
| Mgi Id | MGI:5507905 | Doi | 10.1091/mbc.E12-09-0662 |
| Citation | Han J, et al. (2013) beta-Catenin-dependent lysosomal targeting of internalized tumor necrosis factor-alpha suppresses caspase-8 activation in apoptosis-resistant colon cancer cells. Mol Biol Cell 24(4):465-73 |
| abstractText | The Wnt/beta-catenin pathway is constitutively activated in more than 90% of human colorectal cancer. Activated beta-catenin stimulates cell proliferation and survival, however, its antiapoptotic mechanisms are not fully understood. We show here that activated beta-catenin is required to suppress caspase-8 activation, but only in colon cancer cells that are resistant to tumor necrosis factor-alpha (TNF)-induced apoptosis. We found that lysosomal delivery of internalized TNF occurred at a faster pace in apoptosis-resistant than in apoptosis-sensitive colon cancer cells. Retardation of endosomal trafficking through vacuolar ATPase (V-ATPase) inhibition enhanced caspase-8 activation in apoptosis-resistant but not apoptosis-sensitive cells. Interestingly, knockdown of beta-catenin also prolonged TNF association with the early endosome and enhanced caspase-8 activation in apoptosis-resistant but not apoptosis-sensitive colon cancer cells. In a mouse model of inflammation-associated colon tumors, we found nuclear expression of beta-catenin, resistance to TNF-induced apoptosis, and reactivation of apoptosis in vivo after cotreatment of TNF with a V-ATPase inhibitor. Together these results suggest that activated beta-catenin can facilitate endosomal trafficking of internalized TNF to suppress caspase-8 activation in colon cancer cells. |
