In the first installment of this two-part blog post titled "Apoptosis and Necroptosis: Important factors to identify both types of programmed cell death", the mechanisms by which cell death occurs and ways to identify these pathways were discussed. In this next segment, we focus on the molecular factors regulating the choice between programmed cell death and survival signaling.
Inhibitors of apoptosis proteins (IAPs) regulate cell death and survival signaling via different mechanisms. In mammals, a total of eight IAP family members have been identified1. Among these, X-linked IAP (XIAP), and cellular IAP1 and 2 (cIAP1 and cIAP2) suppress programmed cell death signaling by inhibiting caspase activity2.
Additionally, ubiquitination of the receptor-interacting serine/threonine-protein kinase 1 (RIP1) by IAPs promotes survival and inflammatory signaling downstream of TNFR1 and TLR activation1, 2. For example, following TNFR activation a multiprotein complex is recruited containing RIP and cIAPs. Ubiquitination of RIP1 by cIAPs allows the recruitment of IKK (IkB kinase ),TAK and LUBAC (linear ubiquitin chain assembly complex) complexes, resulting in the activation of inflammatory and survival signaling through nuclear factor kB (NF-kB) 2.
RIP is a known mediator of apoptosis and necroptosis, nevertheless its ubiquitination by IAPs results in the inhibition of cell death pathways and the activation of survival inflammatory signaling3. IAPs are often upregulated in many types of cancer cells, and treatment failure is often associated to their role in the evasion of apoptosis2. Therefore, IAPs have emerged as attractive targets for the development of cancer therapeutic strategies that aim to restore cell death signaling3.
To this end, several IAP antagonists have been developed, all mimicking the endogenous mammalian IAP antagonist Smac/DIABLO (second mitochondria-derived activator of caspases), and thus referred to as Smac-mimetics2. Once targeted by Smac-mimetics, cIAPs are degraded and cell death-apoptotic or -necroptotic complexes are activated in a cell dependent manner4.
In a recent study, Safferthal et al. 2016, demonstrated that the Smac-mimetic BV6, in combination with the caspase inhibitor zVAD.fmk, could induce necroptosis in various acute myeloid leukemia (AML) cell lines4. Induced necroptosis by BV6 in AML cells occurred independently of effects on XIAP, and only as the result of cIAP1 neutralization4. Moreover, in this system BV6 induced necroptosis was dependent on TNFa/TNFR signaling4. TNFa can activate cell survival and death pathways, nevertheless in AML cells, investigators tilted the balance towards necroptosis by targeting IAPs and caspase activities.
Overall, these findings demonstrate that IAPs may serve as effective targets for the modulation of death and survival decisions, allowing the elimination of cancer cells even when apoptosis is impaired.
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- Vasilikos L. et al. (2016). Regulating the balance between necroptosis, apoptosis and inflammation by inhibitors of apoptosis proteins. Immunol. Cell Biol. 95:160–165. DOI:10.1038/icb.2016.118
- Bai L., Smith D. C., & Wang S. (2014). Small-Molecule SMAC Mimetics as New Cancer Therapeutics. Pharmacology & Therapeutics. 144(1), 82–95. http://doi.org/10.1016/j.pharmthera.2014.05.007
- McComb S. et al. (2016). Activation of concurrent apoptosis and necroptosis by SMAC mimetics for the treatment of refractory and relapsed ALL. Sci Transl Med. 8: 339ra370. DOI:10.1126/scitranslmed.aad2986
- Safferthal C., Rohde K., & Fulda S. (2017). Therapeutic targeting of necroptosis by Smac mimetic bypasses apoptosis resistance in acute myeloid leukemia cells. Oncogene 36, 1487-1502. doi:10.1038/onc.2016.310