Targeting XIAP for Promoting Cancer Cell Death—The Story of ARTS and SMAC
Abstract
:1. Introduction
2. IAP-Antagonists, Smac/Diablo, and ARTS
3. Targeting XIAP for Cancer Therapy; Developing Smac and ARTS Small Molecule Mimetics
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Criteria | ARTS | Smac |
---|---|---|
Sub-cellular localization | Mitochondrial outer-membrane [47] | Mitochondrial inner membrane space [43] |
Requirement for MOMP | Acts upstream of MOMP [69]. | Acts downstream of MOMP [43,63] |
Translocation/release from mitochondria to the cytosol | Caspase-independent, occurs within minutes after apoptotic stimuli [69] | Caspase-dependent, occurs hours after apoptotic stimuli [63] |
Binding to BIR3/XIAP | ✓ [78] | ✓ [43] |
Different binding sites within BIR3/XIAP | BIR3/XIAP (aa 272–292) [78,87] | BIR3/XIAP (aa Leu307, Trp310,Glu314,Trp323, Gly306) [43,56] |
Containing different binding sequences to XIAP | Contains a unique C-terminal sequence (AIBM) [78,87] | Contains an IBM (AVPI/F) sequence [43,63,88] |
Degradation of XIAP via the ubiquitin proteasome-system | ✓ [67] | X [71] |
Degradation of cIAPs via the ubiquitin proteasome-system | X [67,77] | ✓ [71] |
Over-expression phenotype | Sufficient to induce apoptotic cell death in a variety of cultured cell lines [52,69] | Enhances apoptosis in combination with additional apoptotic stimuli [43]. |
Knockout (KO) mouse phenotype | Sept4/ARTS deficiency promotes spontaneous tumorigenesis. Sept4/ARTS KO mice develop various types of tumors, mainly lymphoma and leukemia [51,85]. MOMP and the release of Cyto c/Smac from mitochondria are delayed in Sept4/ARTS KO cells [69]. Sept4/ARTS KO mice contain elevated XIAP levels [86]. Sept4/ARTS KO mice have increased numbers of stem and progenitor cells, which are resistant to apoptosis [40,41,85,86]. The resistance of Sept4/ARTS-null hematopoietic stem and progenitor cells (HSPCs) to apoptosis and the cell-autonomous lymphoproliferation is suppressed by the loss of XIAP function in Sept4/ARTS/XIAP double-knockout mice [75]. | Smac deficiency does not cause spontaneous tumorigenesis [73,74,75]. Knockout mice have no detectable apoptotic defects in vivo [73,74]. Loss of Smac in mice led to elevated levels of cIAP1 and cIAP2 and XIAP expression levels remain intact in Smac KO cells [74,75]. Smac-KO cells were resistant to apoptosis induced by NSAIDs and TRAIL [74]. |
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Abbas, R.; Larisch, S. Targeting XIAP for Promoting Cancer Cell Death—The Story of ARTS and SMAC. Cells 2020, 9, 663. https://doi.org/10.3390/cells9030663
Abbas R, Larisch S. Targeting XIAP for Promoting Cancer Cell Death—The Story of ARTS and SMAC. Cells. 2020; 9(3):663. https://doi.org/10.3390/cells9030663
Chicago/Turabian StyleAbbas, Ruqaia, and Sarit Larisch. 2020. "Targeting XIAP for Promoting Cancer Cell Death—The Story of ARTS and SMAC" Cells 9, no. 3: 663. https://doi.org/10.3390/cells9030663