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Smac mimetics can provoke lytic cell death that is neither apoptotic nor necroptotic

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Abstract

Smac mimetics, or IAP antagonists, are a class of drugs currently being evaluated as anti-cancer therapeutics. These agents antagonize IAP proteins, including cIAP1/2 and XIAP, to induce cell death via apoptotic or, upon caspase-8 deficiency, necroptotic cell death pathways. Many cancer cells are unresponsive to Smac mimetic treatment as a single agent but can be sensitized to killing in the presence of the cytokine TNFα, provided either exogenously or via autocrine production. We found that high concentrations of a subset of Smac mimetics could provoke death in cells that did not produce TNFα, despite sensitization at lower concentrations by TNFα. The ability of these drugs to kill did not correlate with valency. These cells remained responsive to the lethal effects of Smac mimetics at high concentrations despite genetic or pharmacological impairments in apoptotic, necroptotic, pyroptotic, autophagic and ferroptotic cell death pathways. Analysis of dying cells revealed necrotic morphology, which was accompanied by the release of lactate dehydrogenase and cell membrane rupture without prior phosphatidylserine exposure implying cell lysis, which occurred over a several hours. Our study reveals that cells incapable of autocrine TNFα production are sensitive to some Smac mimetic compounds when used at high concentrations, and this exposure elicits a lytic cell death phenotype that occurs via a mechanism not requiring apoptotic caspases or necroptotic effectors RIPK3 or MLKL. These data reveal the possibility that non-canonical cell death pathways can be triggered by these drugs when applied at high concentrations.

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Acknowledgements

We thank James Murphy for cell lines and the MLKL antibody, Marco Herold and Hamsa Puthalakath for reagents and assistance with CRISPR gene editing, Suresh Mathivanan for the LC3B antibody and bafilomycin A1 drug, and the LIMS Bioimaging Platform. This study was funded by a Cancer Council Victoria Postdoctoral Fellowship to M.A.M., a grant from The Kids’ Cancer Project and a Grant-in-Aid from the Cancer Council Victoria awarded to C.J.H.

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  1. Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, 3086, Australia

    Mark A. Miles, Sarah Caruso, Amy A. Baxter, Ivan K. H. Poon & Christine J. Hawkins

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  1. Mark A. Miles
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  2. Sarah Caruso
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  3. Amy A. Baxter
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MAM and CJH devised the study and wrote the manuscript text. MAM and SC performed the experiments, AAB and IKHP assisted with planning experiments, MAM analyzed the data and prepared the figures.

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Correspondence to Mark A. Miles.

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Miles, M.A., Caruso, S., Baxter, A.A. et al. Smac mimetics can provoke lytic cell death that is neither apoptotic nor necroptotic. Apoptosis 25, 500–518 (2020). https://doi.org/10.1007/s10495-020-01610-8

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