Document Type

Article

Journal Title

Experimental cell research

Publication Date

1-2011

Volume

317

Abstract

TNF-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.

MeSH Headings

Apoptosis, Caspase 8, Caspase 9, Caspase Inhibitors, Gene Knockdown Techniques, Humans, Inhibitor of Apoptosis Proteins, Protein Processing, Post-Translational, RNA, Small Interfering, Signal Transduction, TNF-Related Apoptosis-Inducing Ligand, Tumor Cells, Cultured, X-Linked Inhibitor of Apoptosis Protein

ISSN

1090-2422

Comments

NOTICE: this is the author’s version of a work that was accepted for publication in Experimental cell research. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Experimental cell research, [317, 1, (2011)] DOI#10.1016/j.yexcr.2010.10.005.

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