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Review
. 2023 Feb 10:13:1124600.
doi: 10.3389/fonc.2023.1124600. eCollection 2023.

Inhibitor of apoptosis proteins as therapeutic targets in bladder cancer

Philipp Wolf  1   2
Affiliations
Review

Inhibitor of apoptosis proteins as therapeutic targets in bladder cancer

Philipp Wolf. Front Oncol. .

Abstract

Evasion from apoptosis is a hallmark of cancer. Inhibitor of apoptosis proteins (IAPs) contribute to this hallmark by suppressing the induction of cell death. IAPs were found to be overexpressed in cancerous tissues and to contribute to therapeutic resistance. The present review focuses on the IAP members cIAP1, cIAP2, XIAP, Survivin and Livin and their importance as potential therapeutic targets in bladder cancer.

Keywords: Livin; Survivin; XIAP; apoptosis; bladder cancer; cIAP1; cIAP2; inhibitor of apoptosis proteins.

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Conflict of interest statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The extrinsic and the intrinsic apoptotic pathways. The Inhibitor of Apoptosis Proteins (IAPs) cIAP1 and 2, XIAP, Survivin and Livin are shown in red. They inhibit both pathways and lead to resistance against apoptosis. Apaf-1, apoptotic protease-activating factor 1; BAD, Bcl-2 antagonist of cell death; Bak, Bcl-2 antagonist/killer; Bax, Bcl-2 associated X protein; Bcl-2, B-cell lymphoma 2; Bcl-w, Bcl-2 like 2; Bcl-xl, B-cell lymphoma extra-large; BID, BH3 interacting domain death agonist; tBid, truncated Bid; BIM, Bcl-2 interacting mediator of cell death; Cyt c, cytochrome C; DISC, death-inducing signaling complex; FADD, Fas-associated protein with death domain; JNK, c-Jun N-terminal kinase; Mcl-1, myeloid cell leukemia sequence; MOMP, mitochondrial outer membrane permeabilization; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B-cells; NOXA, phorbol-12-myristate-13-acetate-induced protein 1; PUMA, p53 upregulated modulator of apoptosis; RIP, receptor interacting protein; Smac, second mitochondria derived activator of caspases; TNF-α, tumor necrosis factor alpha; TRAIL, Tumor Necrosis Factor Related Apoptosis Inducing Ligand; TRADD, tumor necrosis factor receptor type 1-associated death domain protein; TRAF, TNF receptor associated factor.
Figure 2
Figure 2
Schematic representation of the domain structures of the IAP members NIAP (BIRC1), cIAP1 (BIRC2), cIAP2 (BIRC3), XIAP (BIRC4), Survivin (BIRC5), Apollon (BIRC6), Livin (BIRC7) and ILP-2 (BIRC8). Numbers indicate numbers of amino acids of each IAP. The baculovirus IAP repeat (BIR) domain can bind and inhibit caspases. The, really interesting new gene (RING) domain has E3 ligase activity and for (auto-) ubiquitination of proteins for subsequent proteasomal degradation. The caspase activation and recruitment domain (CARD) domain mediates the autoinhibition of the E3 ubiquitin ligase activity by preventing RING dimerization. Other functional domains of IAPs comprise the ubiquitin associated domain (UBA) for binding to polyubiquitin chains for cell survival, activation of NF-kB signaling and proteasomal degradation, the ubiquitin conjugation domain (UBC) with E2 ubiquitin conjugating ligase activity and the neuronal apoptosis inhibitory protein domain (NACHT) with nucleoside-triphosphatase (NTPase) activity. BIR, aculorvirus IAP repeat; CARD, caspase recruitment domain; LRR, leucine-rich repeat; NACHT, neuronal apoptosis inhibitory protein; UBA, ubiquitin-associated.
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Grants and funding

We acknowledge support by the Open Access Publication Fund of the University of Freiburg.