| Autor: |
Abhari BA; Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstr. 3a, 60528, Frankfurt, Germany., McCarthy N; Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstr. 3a, 60528, Frankfurt, Germany., Agostinis P; Cell Death Research and Therapy Unit, Department of Cellular and Molecular Medicine, KU Leuven, 3000, Leuven, Belgium., Fulda S; Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstr. 3a, 60528, Frankfurt, Germany. simone.fulda@kgu.de.; German Cancer Consortium (DKTK), Partner Site Frankfurt, Heidelberg, Germany. simone.fulda@kgu.de.; German Cancer Research Center (DKFZ), Heidelberg, Germany. simone.fulda@kgu.de. |
| Abstrakt: |
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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