Cellular inhibitor of apoptosis 1 (cIAP-1) degradation by caspase 8 during TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis

INF-related apoptosis-inducing ligand (TRAIL) is a potential chemotherapeutic agent with high selectivity for malignant cells Many tumors however are resistant to TRAIL cytotoxicity Although cellular inhibitors of apoptosis 1 and 2 (cIAP-1 and -2) are often over-expressed in cancers their role in mediating TRAIL resistance remains unclear Here we demonstrate that TRAIL-Induced apoptosis of liver cancer cells is associated with degradation of cIAP-1 and X-linked IAP (XIAP) whereas cIAP-2 remains unchanged Lower concentrations of TRAIL causing minimal or no apoptosis do not alter cIAP-1 or XIAP protein levels Silencing of cIAP-1 expression but not XIAP or cIAP-2 as well as co-treatment with a second mitochondrial activator of caspases (SMAC) mimetic (which results in rapid depletion of cIAP-1) sensitizes the cells to TRAIL TRAIL-induced loss of cIAP-1 and XIAP requires caspase activity In particular caspase 8 knockdown stabilizes both cIAP-1 and XIAP while caspase 9 knockdown prevents XIAP but not cIAP-1 degradation Cell-free experiments confirmed cIAP-1 is a substrate for caspase 8 with likely multiple cleavage sites These results suggest that TRAIL-mediated apoptosis proceeds through caspase 8-dependent degradation of cIAP-1 Targeted depletion of cIAP-1 by SMAC mimetics in conjunction with TRAIL may be beneficial for the treatment of human hepatobiliary malignancies (C) 2010 Elsevier Inc All rights reserved