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NF-κB contributes to Smac mimetic-conferred protection from tunicamycin-induced apoptosis

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Abstract

Smac mimetics that deplete cellular inhibitor of apoptosis (cIAP) proteins have been shown to activate Nuclear Factor-kappa B (NF-κB). Here, we report that Smac mimetic-mediated activation of NF-κB contributes to the rescue of cancer cells from tunicamycin (TM)-triggered apoptosis. The prototypic Smac mimetic BV6 activates non-canonical and canonical NF-κB pathways, while TM has little effect on NF-κB signaling. Importantly, ectopic expression of dominant-negative IκBα superrepressor (IκBα-SR), which inhibits canonical and non-canonical NF-κB activation, significantly reversed this BV6-imposed protection against TM. Similarly, transient or stable knockdown of NF-κB-inducing kinase, which accumulated upon exposure to BV6 alone and in combination with TM, significantly counteracted BV6-mediated inhibition of TM-induced apoptosis. Interestingly, while cIAP2 was initially degraded upon BV6 treatment, it was subsequently upregulated in an NF-κB-dependent manner, as this restoration of cIAP2 expression was abolished in IκBα-SR-overexpressing cells. Interestingly, upon exposure to TM/BV6 apoptosis was significantly increased in cIAP2 knockdown cells. Furthermore, NF-κB inhibition partially prevented BV6-stimulated expression of Mcl-1 upon TM treatment. Consistently, Mcl-1 silencing significantly inhibited BV6-mediated protection from TM-induced apoptosis. Thus, NF-κB activation by Smac mimetic contributes to Smac mimetic-mediated protection against TM-induced apoptosis.

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Acknowledgements

We thank Dr. D. Vucic (Genentech Inc., South San Francisco, CA) for providing BV6, Prof. M. Leverkus (Mannheim, Germany) for cIAP1/2 DKO MEFs, and C. Hugenberg for expert secretarial assistance.

Funding

This work has been partially supported by grants from the Deutsche Forschungsgemeinschaft and BMBF (to S.F.). Furthermore, this project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No. 675448 (to S.F, P.A. and N. McC.). This paper presents research results of the IUAP7/32, funded by the Interuniversity Attraction Poles Program, initiated by the Belgian State, Science Policy Office (to S.F. and P.A.).

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Authors and Affiliations

  1. Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstr. 3a, 60528, Frankfurt, Germany

    Behnaz Ahangarian Abhari, Nicole McCarthy & Simone Fulda

  2. German Cancer Consortium (DKTK), Partner Site Frankfurt, Heidelberg, Germany

    Simone Fulda

  3. German Cancer Research Center (DKFZ), Heidelberg, Germany

    Simone Fulda

  4. Cell Death Research and Therapy Unit, Department of Cellular and Molecular Medicine, KU Leuven, 3000, Leuven, Belgium

    Patrizia Agostinis

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  1. Behnaz Ahangarian Abhari
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  2. Nicole McCarthy
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Correspondence to Simone Fulda.

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Abhari, B.A., McCarthy, N., Agostinis, P. et al. NF-κB contributes to Smac mimetic-conferred protection from tunicamycin-induced apoptosis. Apoptosis 24, 269–277 (2019). https://doi.org/10.1007/s10495-018-1507-2

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