β-Catenin–dependent lysosomal targeting of internalized tumor necrosis factor-α suppresses caspase-8 activation in apoptosis-resistant colon cancer cells

• DOI: 10.1091/mbc.e12-09-0662
• Publication Date: 2012-12-22T08:22:44Z
• Authors: Jinbo Han; Priya Sridevi; Michael Ramirez; Kirsten J. Ludwig; Jean Y. J. Wang
• Keywords: Male; 0301 basic medicine; Vacuolar Proton-Translocating ATPases; Drug Resistance; Apoptosis; Inbred C57BL; Small Interfering; Medical and Health Sciences; Mice; 03 medical and health sciences; 2.1 Biological and endogenous factors; Animals; Humans; Aetiology; Enzyme Inhibitors; RNA, Small Interfering; beta Catenin; Cancer; Cell Proliferation; Neoplastic; Caspase 8; Tumor Necrosis Factor-alpha; Articles; Biological Sciences; HCT116 Cells; Endocytosis; Colo-Rectal Cancer; 3. Good health; Gene Expression Regulation, Neoplastic; Mice, Inbred C57BL; Protein Transport; Gene Expression Regulation; Drug Resistance, Neoplasm; Biochemistry and cell biology; Colonic Neoplasms; Neoplasm; RNA; Biochemistry and Cell Biology; Digestive Diseases; Lysosomes; Developmental Biology; Signal Transduction

The Wnt/β-catenin pathway is constitutively activated in more than 90% of human colorectal cancer. Activated β-catenin stimulates cell proliferation and survival, however, its antiapoptotic mechanisms are not fully understood. We show here that activated β-catenin is required to suppress caspase-8 activation, but only in colon cancer cells that are resistant to tumor necrosis factor-α (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 β-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 β-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 β-catenin can facilitate endosomal trafficking of internalized TNF to suppress caspase-8 activation in colon cancer cells.