Cited by 1,218Cell death mechanisms and regulationNF-κB Signaling PathwaysUbiquitin and proteasome pathways

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IAP Antagonists Induce Autoubiquitination of c-IAPs, NF-κB Activation, and TNFα-Dependent Apoptosis

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Varfolomeev, Eugene, Blankenship, John W., Wayson, Sarah M., Fedorova, Anna V., Kayagaki, Nobuhiko, Garg, Parie, Zobel, Kerry, Dynek, Jasmin N., Elliott, Linda O., Wallweber, Heidi J.A., Flygare, John A., Fairbrother, Wayne J., Deshayes, Kurt, Dixit, Vishva M., Vucic, Domagoj·2007·Cell

DOI 10.1016/j.cell.2007.10.030

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Abstract

Inhibitor of apoptosis (IAP) proteins are antiapoptotic regulators that block cell death in response to diverse stimuli. They are expressed at elevated levels in human malignancies and are attractive targets for the development of novel cancer therapeutics. Herein, we demonstrate that small-molecule IAP antagonists bind to select baculovirus IAP repeat (BIR) domains resulting in dramatic induction of auto-ubiquitination activity and rapid proteasomal degradation of c-IAPs. The IAP antagonists also induce cell death that is dependent on TNF signaling and de novo protein biosynthesis. Additionally, the c-IAP proteins were found to function as regulators of NF-kappaB signaling. Through their ubiquitin E3 ligase activities c-IAP1 and c-IAP2 promote proteasomal degradation of NIK, the central ser/thr kinase in the noncanonical NF-kappaB pathway.

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“However, if cIAPs are antagonized, TNF ligation to TNFR1 causes the activation of caspase-8 to initiate the apoptotic program (Varfolomeev et al., 2007; Vince et al., 2007).”
Background
Clinical Positioning of the IAP Antagonist Tolinapant (ASTX660) in Colorectal Cancer
Crawford, N., Stott, K. J., Sessler, T., McCann, C. K., McDaid, W. J., Lees, A., Latimer, C. H., Fox, J. P., Munck, J. M., Smyth, T., et al. (2021) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-20-1050 · Cited by 33
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“In the absence of stimulation, newly synthesized NIK is constantly proteosomally degraded (Varfolomeev et al., 2007) due to its rapid ubiquitination by TNF receptor-associated factor 3 (TRAF3) (Zarnegar et al., 2008), TRAF2 and their interaction partners, cellular inhibitor of apoptosis 1 and 2…”
Background
APPL1 regulates basal NF-κB activity by stabilizing NIK
Hupalowska, A., Pyrzyńska, B., & Miączyńska, M. (2012) · Journal of Cell Science · doi:10.1242/jcs.105171 · Cited by 32
Linear polyubiquitin chains
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Small molecule-mediated protein knockdown as a new approach to drug discovery
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The SMAC mimetic BV6 sensitizes colorectal cancer cells to ionizing radiation by interfering with DNA repair processes and enhancing apoptosis
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“Smac mimetics induce activation of both canonical and noncanonical NF-kB pathways, regardless of whether the cells are sensitive or resistant to Smac mimetic–mediated growth inhibition (9, 10).”
SMG1 and NIK regulate apoptosis induced by Smac mimetic compounds
Cheung, H. H., Jean, M. S., Beug, S. T., Mrad, R. L., LaCasse, E. C., Baird, S. D., Stojdl, D. F., Screaton, R. A., & Korneluk, R. G. (2011) · Cell Death and Disease · doi:10.1038/cddis.2011.25 · Cited by 32
“previously suggested role of NIK as a pro-death regulator functioning to promote the production of TNFa.(16,17) Furthermore, a siRNA screen that simultaneously targeted NIK in combination with the kinome revealed that the additional loss”
Chronicles of a death foretold: Dual sequential cell death checkpoints in TNF signaling
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Correction: OTUB1 prevents lethal hepatocyte necroptosis through stabilization of c-IAP1 during murine liver inflammation
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Sensitization of human bladder tumor cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis with a small molecule IAP antagonist
Griffith, T. S., Kucaba, T. A., O’Donnell, M. A., Burns, J., Benetatos, C. A., McKinlay, M. A., Condon, S. M., & Chunduru, S. K. (2010) · APOPTOSIS · doi:10.1007/s10495-010-0535-3 · Cited by 31
Conjugation to a SMAC mimetic potentiates sigma-2 ligand induced tumor cell death in ovarian cancer
Garg, G., Vangveravong, S., Zeng, C., Collins, L. I., Hornick, M. C., Hashim, Y. M., Piwnica-Worms, D. R., Powell, M. A., Mutch, D. G., Mach, R. H., et al. (2014) · Molecular Cancer · doi:10.1186/1476-4598-13-50 · Cited by 31
Effect of longevity genetic variants on the molecular aging rate
Gurinovich, A., Song, Z., Zhang, W., Federico, A. N., Monti, S., Andersen, S. L., Jennings, L. L., Glass, D. J., Barzilai, N., Milman, S., et al. (2021) · GeroScience · doi:10.1007/s11357-021-00376-4 · Cited by 28
Soluble TL 1A is sufficient for activation of death receptor 3
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Oncogenic activity of BIRC 2 and BIRC 3 mutants independent of nuclear factor‐κB‐activating potential
Yamato, A., Soda, M., Ueno, T., Kojima, S., Sonehara, K., Kawazu, M., Sai, E., Yamashita, Y., Nagase, T., & Mano, H. (2015) · Cancer Science · doi:10.1111/cas.12726 · Cited by 31
The seventh zinc finger motif of A20 is required for the suppression of TNF‐α‐induced apoptosis
Yamaguchi, N., & Yamaguchi, N. (2015) · FEBS Letters · doi:10.1016/j.febslet.2015.04.022 · Cited by 33
“Thus, cells were treated with the cIAP1/2 antagonist MV-1, which promotes autoubiquitination and degradation of cIAP1/2 [31], prior to TNF-a stimulation.”
Background
Deregulated apoptosis signaling in core-binding factor leukemia differentiates clinically relevant, molecular marker-independent subgroups
Lück, S. C., Russ, A. C., Botzenhardt, U., Paschka, P., Schlenk, R. F., Döhner, H., Fulda, S., Döhner, K., & Bullinger, L. (2011) · Leukemia · doi:10.1038/leu.2011.154 · Cited by 31
Estrogen Promotes Breast Cancer Cell Survival in an Inhibitor of Apoptosis (IAP)-dependent Manner
Stanculescu, A., Bembinster, L. A., Borgen, K. R., Bergamaschi, A., Wiley, E. L., & Frasor, J. M. (2010) · Hormones and Cancer · doi:10.1007/s12672-010-0018-6 · Cited by 31
“Although cIAP1 and cIAP2 are less potent at inhibiting caspase activity, SMs can facilitate autoubiquitination and degradation of cIAP1 and cIAP2 [20].”
Nuclear Factor-κB-inducing Kinase (NIK) Contains an Amino-terminal Inhibitor of Apoptosis (IAP)-binding Motif (IBM) That Potentiates NIK Degradation by Cellular IAP1 (c-IAP1)
Lee, S. H., Challa-Malladi, M., Bratton, S. B., & Wright, C. W. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.587808 · Cited by 32
Smac mimetic-induced caspase-independent necroptosis requires RIP1 in breast cancer
Jin, G., Lan, Y., Han, F., Sun, Y., Liu, Z., Zhang, M., Liu, X., Zhang, X., Hu, J., Liu, H., et al. (2015) · Molecular Medicine Reports · doi:10.3892/mmr.2015.4542 · Cited by 30
“Upon binding to cIAP1, LCL161 triggers the autoubiquitination and proteasomal degradation of cIAP1, which is followed by nuclear factor-κ B activation and tumor necrosis factor-α -dependent apoptosis (27).”
Perfluorodecanoic acid stimulates NLRP3 inflammasome assembly in gastric cells
Zhou, X., Dong, T., Fan, Z., Peng, Y., Zhou, R., Wang, X., Song, N., Han, M., Fan, B., Jia, J., et al. (2017) · Scientific Reports · doi:10.1038/srep45468 · Cited by 29
Therapeutic opportunities based on caspase modulation
Fulda, S. (2017) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2017.12.008 · Cited by 30
Proteasome inhibition blocks necroptosis by attenuating death complex aggregation
Ali, M., & Mocarski, E. S. (2018) · Cell Death and Disease · doi:10.1038/s41419-018-0371-x · Cited by 31
Key necroptotic proteins are required for Smac mimetic-mediated sensitization of cholangiocarcinoma cells to TNF-α and chemotherapeutic gemcitabine-induced necroptosis
Akara-amornthum, P., Lomphithak, T., Choksi, S., Tohtong, R., & Jitkaew, S. (2020) · PLoS ONE · doi:10.1371/journal.pone.0227454 · Cited by 31
The Deubiquitinating Enzyme USP20 Regulates the TNFα-Induced NF-κB Signaling Pathway through Stabilization of p62
Ha, J., Kim, M., Seo, D., Park, J. S., Lee, J., Lee, J., & Park, S. H. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21093116 · Cited by 29
“HT29 colon cancer cells are widely used to detect necroptosis by co-treatment with TNFα, BV6 (IAP inhibitor) and z-VAD-fmk (caspase inhibitor) [31], and MLKL (mixed lineage kinase domain like pseudokinase) phosphorylation is used as a marker of necroptosis [32].”
Method
A small-molecule ARTS mimetic promotes apoptosis through degradation of both XIAP and Bcl-2
Mamriev, D., Abbas, R., Klingler, F., Kagan, J., Kfir, N., Donald, A., Weidenfeld, K., Sheppard, D. W., Barkan, D., & Larisch, S. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-2670-2 · Cited by 31
Progress of small molecules for targeted protein degradation: PROTACs and other technologies
Zhao, H., Xin, M., & Zhang, S. (2023) · Drug Development Research · doi:10.1002/ddr.22026 · Cited by 31
“Additionally, 23 (Figure 9) was reported to be a pan‐IAP antagonist on the basis of structure‐based drug design strategy (Varfolomeev et al., 2007).”
Background
CLL cells are resistant to smac mimetics because of an inability to form a ripoptosome complex
Maas, C., Tromp, J. M., van Laar, J., Thijssen, R., Elias, J. A., Malara, A., Krippner‐Heidenreich, A., Silke, J., van Oers, M. H. J., & Eldering, E. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.305 · Cited by 30
Recognition of Smac‐mimetic compounds by the BIR domain of cIAP1
Cossu, F., Malvezzi, F., Canevari, G., Mastrangelo, E., Lecis, D., Delia, D., Seneci, P., Scolastico, C., Bolognesi, M., & Milani, M. (2010) · Protein Science · doi:10.1002/pro.523 · Cited by 30
RIP1 Protein-dependent Assembly of a Cytosolic Cell Death Complex Is Required for Inhibitor of Apoptosis (IAP) Inhibitor-mediated Sensitization to Lexatumumab-induced Apoptosis
Basit, F., Humphreys, R. C., & Fulda, S. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.398966 · Cited by 31
“Because apoptosis triggered by monotherapy with IAP inhibitors has been attributed to a TNF -mediated autocrine cell death loop that drives activation of the caspase cascade (5, 6), we next tested whether the addition of the TNF -blocking antibody Enbrel rescues cells from IAP inhibitor- and lexatumumab-induced apopto…”
BackgroundMethodInfluential
Caspase-10: a molecular switch from cell-autonomous apoptosis to communal cell death in response to chemotherapeutic drug treatment
Mohr, A., Deedigan, L., Jencz, S., Mehrabadi, Y., Houlden, L., Albarenque, S. M., & Zwacka, R. M. (2017) · Cell Death and Differentiation · doi:10.1038/cdd.2017.164 · Cited by 28
Sensitization of glioblastoma cells to TRAIL-induced apoptosis by IAP- and Bcl-2 antagonism
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Authors: Varfolomeev, E., Blankenship, J. W., Wayson, S. M., Fedorova, A. V., Kayagaki, N., Garg, P., Zobel, K., Dynek, J. N., Elliott, L. O., Wallweber, H. J. A., Flygare, J. A., Fairbrother, W. J., Deshayes, K., Dixit, V. M., & Vucic, D.
Affiliations: Genentech (US)
Corresponding author: Dixit, Vishva M.
Vucic, Domagoj
ORCID: Varfolomeev, Eugene
Blankenship, John W.
Fedorova, Anna V.
Kayagaki, Nobuhiko
Zobel, Kerry
Fairbrother, Wayne J.
Dixit, Vishva M.
Vucic, Domagoj
Venue: Cell
Publisher: Elsevier BV
Published: 2007-11
Volume: 131
Issue: 4
Pages: 669-681
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2007.10.030
OpenAlex: W2064299413
Cited by: 1,218
References: 51
Citations by year: 2026: 28 · 2025: 24 · 2024: 39 · 2023: 45 · 2022: 41 · 2021: 60 · 2020: 59 · 2019: 54 · 2018: 69 · 2017: 64 · 2016: 78 · 2015: 80 · 2014: 100 · 2013: 78 · 2012: 71
FWCI: 33.22
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 2085 d)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
Lund University Publications (Lund University) (submittedVersion)
Funders: Genentech
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords: inhibitor of apoptosis proteins, IAP antagonists, cIAP1, cIAP2, autoubiquitination, proteasomal degradation, NF-κB signaling, non-canonical NF-κB signaling, NIK, TNF signaling, apoptosis, cancer therapeutics
MeSH terms: Animals, Cell Line, Humans, Neoplasms, Tumor Necrosis Factor-alpha, Molecular Structure, Signal Transduction, NF-kappa B, Apoptosis, Protein Structure, Tertiary, Polyubiquitin, Proteasome Endopeptidase Complex, Inhibitor of Apoptosis Proteins, Mice, Ubiquitination

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IAP Antagonists Induce Autoubiquitination of c-IAPs, NF-κB Activation, and TNFα-Dependent Apoptosis

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