Reawakening the cellular death program in neoplasia through the therapeutic blockade of IAP function

Abstract

Recent studies have shown that members of the inhibitor of apoptosis (IAP) protein family are highly expressed in several classes of cancer. The primary implication of these findings is that the elevated expression of IAPs is not coincidental but actually participates in oncogenesis by helping to allow the malignant cell to avoid apoptotic cell death. This concept, together with the discovery of several IAP-regulatory proteins that use a conserved mode of action, has stimulated a major effort by many research groups to devise IAP-targeting strategies as a means of developing novel antineoplastic drugs. In this Review, we consider the evidence both for and against the IAPs being valid therapeutic targets, and we describe the types of strategies being used to neutralize their functions.

Figure 1

The IAP family members. (A) All IAP members contain 1 or more imperfect baculovirus iap repeats (BIRs), the defining motif of the IAP family. Many of the IAP proteins also posses an E3 ubiquitin ligase RING domain at the carboxy terminus. (B) XIAP can bind and enzymatically inhibit caspase-3, caspase-7, and caspase-9. XIAP binds caspase-3 and caspase-7 at a sequence directly upstream of BIR2, while it binds caspase-9 in a region of BIR3. CARD, caspase recruitment domain.

Figure 2

XIAP in apoptosis regulation. Following an apoptotic stimulus, enzymes known as caspases are activated and initiate a cascade leading to the destruction of the cell. The caspases are activated via 2 main avenues, by the stimulation of death receptors (the extrinsic pathway) and by the release of apoptogenic factors from the mitochondria (the intrinsic pathway). XIAP regulates both the extrinsic and the intrinsic apoptotic pathways through direct inhibition of caspase-3 and caspase-9.

Figure 3

Smac/DIABLO displaces caspase-9 from BIR3 of XIAP. (A) Crystal structure of processed caspase-9 bound to BIR3 of XIAP. The purple peptide represents the first 4 amino acids that contact XIAP, with the amino terminus near the orange residue of XIAP. Coordinates were obtained from Brookhaven Protein Databank file 1NW9 (82). (B) NMR structure of the Smac/DIABLO IBM (purple peptide with the amino terminus near the orange residue of XIAP) bound to the same groove on BIR3 of XIAP that binds caspase-9, thus abrogating the ability of XIAP to block caspase-9 activity. Coordinates were obtained from Brookhaven Protein Databank file 1G3F (83). The 4 residues displayed in van der Waals radii spacefill on XIAP BIR3 are Gly306 (red), Leu307 (green), Trp310 (yellow), and Glu314 (orange). These 4 residues are critical in forming the Smac/DIABLO–binding groove on XIAP BIR3 (84). Images were created using Protein Explorer (85, 86).