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

Apoptosis. 2019 Apr;24(3-4):269-277. doi: 10.1007/s10495-018-1507-2.

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.

Keywords: Apoptosis; Cell death; NF-κB; Smac; Tunicamycin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / metabolism*
  • Cell Line
  • HEK293 Cells
  • Humans
  • Inhibitor of Apoptosis Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mitochondrial Proteins / metabolism*
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • NF-KappaB Inhibitor alpha / metabolism
  • NF-kappa B / metabolism*
  • Signal Transduction / drug effects
  • Tunicamycin / pharmacology*
  • Up-Regulation / drug effects

Substances

  • Apoptosis Regulatory Proteins
  • DIABLO protein, human
  • Inhibitor of Apoptosis Proteins
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • Myeloid Cell Leukemia Sequence 1 Protein
  • NF-kappa B
  • Tunicamycin
  • NF-KappaB Inhibitor alpha