A Review of the Current Impact of Inhibitors of Apoptosis Proteins and Their Repression in Cancer

Abstract

The Inhibitor of Apoptosis (IAP) family possesses the ability to inhibit programmed cell death through different mechanisms; additionally, some of its members have emerged as important regulators of the immune response. Both direct and indirect activity on caspases or the modulation of survival pathways, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), have been implicated in mediating its effects. As a result, abnormal expression of inhibitor apoptosis proteins (IAPs) can lead to dysregulated apoptosis promoting the development of different pathologies. In several cancer types IAPs are overexpressed, while their natural antagonist, the second mitochondrial-derived activator of caspases (Smac), appears to be downregulated, potentially contributing to the acquisition of resistance to traditional therapy. Recently developed Smac mimetics counteract IAP activity and show promise in the re-sensitization to apoptosis in cancer cells. Given the modest impact of Smac mimetics when used as a monotherapy, pairing of these compounds with other treatment modalities is increasingly being explored. Modulation of molecules such as tumor necrosis factor-α (TNF-α) present in the tumor microenvironment have been suggested to contribute to putative therapeutic efficacy of IAP inhibition, although published results do not show this consistently underlining the complex interaction between IAPs and cancer.

Keywords: NF-κB; SMAC mimetics; TNF-α; apoptosis; endoplasmic reticulum stress; inhibitor of apoptosis proteins.

Figure 1

Schematic representation of the IAP family members’ structure. The nomenclature, length, and domains of the different proteins are shown. Abbreviations: BIR (Baculoviral IAP Repeat), NOD (Nucleotide-binding and Oligomerization Domain), LRR (Leucine Rich Repeat), UBA (Ubiquitin-Associated), CARD (Caspase-Associated Recruitment Domain), RING (Really Interesting New Gene), UBC (Ubiquitin-conjugating).

Figure 2

Participation of cIAPs in NF-κB classical and alternative pathways. E3 ligase activity from IAPs’ RING domain allow the addition of Ub residues onto proteins involved in these signaling cascades. In the classical pathway, cIAPs have a positive regulatory function while they exhibit negative regulation in the alternative pathway. Abbreviations: NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), TNF-α (tumor necrosis factor-α), RIPK (Receptor-interacting serine/threonine-protein kinase), TRADD (TNF Receptor Associated Death Domain), TRAF (TNF Receptor Associated Factor), cIAP (cellular-Inhibitor of Apoptosis Protein), LUBAC (Linear Ubiquitination Assembly Complex), IKK (IκB Kinase), NIK (NF-κB-inducing kinase), Ub (ubiquitin).

Figure 3

The role of Smac mimetics in the regulation of TNF-α dynamics and the promotion of apoptosis. The inhibition of cIAPs alters NF-κB pathways. The classical NF-κB pathway is pushed towards caspase-8 dependent apoptosis through the formation of RIPK-FADD-Caspase-8 complex and it is fed by the production of TNF-α in the alternative pathway. Abbreviations: TNF-α (Tumor Necrosis Factor-α), TNFR (Tumor Necrosis Factor Receptor), cIAP (cellular- Inhibitor of Apoptosis Protein), RIPK (Receptor-interacting serine/threonine-protein kinase), FADD (Fas-associated protein with death domain), TRAF (TNF receptor associated factor), NIK (NF-κB-inducing kinase), NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells).

Figure 4

ER stress and Smac mimetics. Abbreviations, ER stress, endoplasmic reticulum stress; IAPs, inhibitor apoptosis proteins; UPR, unfolded protein response.