Inhibitor of Apoptosis Proteins: Promising Targets for Cancer Therapy

Abstract

Cancer is a disease in which normal physiological processes are imbalanced, leading to tumour formation, metastasis and eventually death. Recent biological advances have led to the advent of targeted therapies to complement traditional chemotherapy and radiotherapy. However, a major problem still facing modern medicine is resistance to therapies, whether targeted or traditional. Therefore, to increase the survival rates of cancer patients, it is critical that we continue to identify molecular targets for therapeutic intervention. The Inhibitor of Apoptosis (IAP) proteins act downstream of a broad range of stimuli, such as cytokines and extracellular matrix interactions, to regulate cell survival, proliferation and migration. These processes are dysregulated during tumourigenesis and are critical to the metastatic spread of the disease. IAPs are commonly upregulated in cancer and have therefore become the focus of much research as both biomarkers and therapeutic targets. Here we discuss the roles that IAPs may play in cancer, and the potential benefits and pitfalls that targeting IAPs could have in the clinic.

Keywords: Apoptosis; Cancer therapy; Clinical trials; Cytokines; Extracellular matrix; IAP.

Figure 1. Schematic representation of human IAPs

IAPs contain between one and three Baculovirus IAP repeat (BIR) domains, a 70–80 amino acid Zinc-binding motif. Five of the 8 IAPs possess a carboxy-terminal RING (really interesting new gene) domain that functions as an E3 ligase, capable of self-ubiquitination and ubiquitination of associated proteins. BRUCE lacks a RING domain but possesses an Ubiquitin-Conjugating Domain (UBC) that can induce ubiquitination. XIAP and cIAPs have an Ubiquitin-Associated (UBA) ubiquitin-binding domain that is important for their signalling function [67,98]. In addition cIAP1 and cIAP2 contain a Caspase Recruitment Domain (CARD) that can mediate homotypic interactions [99]. NAIP possesses a LRR (Leucine-Rich Repeat) and a NOD (nucleotide-binding oligomerisation domain), which have been implicated in microbial pathogen recognition. Survivin contains a COIL (coil-coiled) domain, which is involved in binding to chromosomal paasenger proteins INCENP and borealin.

Figure 2. Summary of IAP functions

A selection of the pathways in which IAPs function to regulate apoptosis, survival, cell cycle and migration: A –Regulation of caspases, B – TNFα signalling, C – Non-canonical NF-κBD – TGFβ signalling, E –ECM interactions, F – Cell cycle, G – Migration.