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Review
. 2022 Jun 23:12:922596.
doi: 10.3389/fonc.2022.922596. eCollection 2022.

ILP-2: A New Bane and Therapeutic Target for Human Cancers

Zhiliang Zhang  1   2 , Siqi Xiang  1   2 , Ruxia Cui  1   2 , Hang Peng  1   2 , Roy Mridul  1   2 , Mingjun Xiang  1   2
Affiliations
Review

ILP-2: A New Bane and Therapeutic Target for Human Cancers

Zhiliang Zhang et al. Front Oncol. .

Abstract

Inhibitor of apoptosis protein-related-like protein-2 (ILP-2), also known as BIRC-8, is a member of the inhibitor of apoptosis protein (IAPs) family, which mainly encodes the negative regulator of apoptosis. It is selectively overexpressed in a variety of human tumors and can help tumor cells evade apoptosis, promote tumor cell growth, increase tumor cell aggressiveness, and appears to be involved in tumor cell resistance to chemotherapeutic drugs. Several studies have shown that downregulation of ILP-2 expression increases apoptosis, inhibits metastasis, reduces cell growth potential, and sensitizes tumor cells to chemotherapeutic drugs. In addition, ILP-2 inhibits apoptosis in a unique manner; it does not directly inhibit the activity of caspases but induces apoptosis by cooperating with other apoptosis-related proteins. Here, we review the current understanding of the various roles of ILP-2 in the apoptotic cascade and explore the use of interfering ILP-2, and the combination of related anti-tumor agents, as a novel strategy for cancer therapy.

Keywords: IAPS; ILP-2; apoptosis; caspases; migration; tumor therapy.

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Conflict of interest statement

The authors declare 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
Schematic diagram of domain structure of human IAP proteins. BIR, baculovirus IAP repeats; CARD, caspase activating and recruitment domain; RING, ring zinc-finger. c-IAP1, cellular Inhibitor of apoptosis protein; c-IAP2, cellular Inhibitor of apoptosis protein; ML-IAP, livin/melanoma-Inhibitor of apoptosis protein; XIAP, Survivin, X-linked Inhibitor of apoptosis protein; NAIP, Neuronal apoptosis inhibitory protein; BRUCE, Baculoviral IAP repeat-containing ubiquitin-conjugating enzym; ILP-2, Inhibitor of apoptosis protein-like protein-2.
Figure 2
Figure 2
ILP-2 protein structure and function. ILP-2 (also kwon as BIRC8) protein structure presents 236 amino acids and is composed of a Baculovirus IAP Repeat (BIR) domain, an Ubiquitin-associated (UBA) domain, and a RING finger domain. Each structural domain of ILP-2 is capable of binding to the corresponding protein to perform the relevant function. The numbers refer to amino acids.
Figure 3
Figure 3
Schematic diagram of the major apoptotic signaling pathways related to ILP-2. ILP-2, which is highly expressed in tumor cells, is one of the high-risk factors for tumor discovery and development, and can activate multiple apoptosis-inhibiting signaling pathways and regulate the expression and activity of various apoptosis-related proteins to inhibit apoptosis.
Figure 4
Figure 4
Regulation of cell proliferation, migration and cell cycle by ILP-2. ILP-2 activates Bcl-2, ECM1-Akt signaling pathway, inhibits CHK2 expression and promotes cell proliferation, autophagy, migration as well as cell cycle transition.
Figure 5
Figure 5
Scheme of therapeutic approaches potentially triggered by ILP-2. Multiple changes of apoptotic proteins contribute to cancer development and progression, and treatment targeting ILP-2 can be developed to restore normal sensitivity to apoptotic stimuli and, therefore, repress cancer.
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