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

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