NF-[kappa]B contributes to Smac mimetic-conferred protection from tunicamycin-induced apoptosis

• Published in: Apoptosis (London) 2019-04, Vol.24 (3-4), p.269
• Main Authors: Abhari, Behnaz Ahangarian, McCarthy, Nicole, Agostinis, Patrizia, Fulda, Simone
• Format: Article
• Language: English
• Subjects: Apoptosis; Proteins
• ISSN: 1360-8185
• DOI: 10.1007/s10495-018-1507-2

Smac mimetics that deplete cellular inhibitor of apoptosis (cIAP) proteins have been shown to activate Nuclear Factor-kappa B (NF-[kappa]B). Here, we report that Smac mimetic-mediated activation of NF-[kappa]B contributes to the rescue of cancer cells from tunicamycin (TM)-triggered apoptosis. The prototypic Smac mimetic BV6 activates non-canonical and canonical NF-[kappa]B pathways, while TM has little effect on NF-[kappa]B signaling. Importantly, ectopic expression of dominant-negative I[kappa]B[alpha] superrepressor (I[kappa]B[alpha]-SR), which inhibits canonical and non-canonical NF-[kappa]B activation, significantly reversed this BV6-imposed protection against TM. Similarly, transient or stable knockdown of NF-[kappa]B-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-[kappa]B-dependent manner, as this restoration of cIAP2 expression was abolished in I[kappa]B[alpha]-SR-overexpressing cells. Interestingly, upon exposure to TM/BV6 apoptosis was significantly increased in cIAP2 knockdown cells. Furthermore, NF-[kappa]B 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-[kappa]B activation by Smac mimetic contributes to Smac mimetic-mediated protection against TM-induced apoptosis.