2.2.4 X-chromosome-linked inhibitors of apoptosis (XIAP)
Inhibitors of apoptosis protein cIAP1 and cIAP2 have increased copy number and expression levels in primary diffuse large B-cell lymphoma (DLBCL) tissues, while a second mitochondrial-derived cysteine aspartase (Smac) mimetic activator was designed to antagonize IAP proteins. Anna Dietz et al 42 investigated Smac mimetic BV6 could enhance the proteasome sensitivity of DLBCL cells and analyzed the molecular mechanism. Activation of BAX and BAK co-triggered by BV6 and the inhibitor Carfilzomib (CFZ) promoted cell death.
BV6/CFZ induces mitochondria-mediated apoptosis mainly by activating BAX and BAK. Pretreatment with the cysteinase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD.fmk) rescued BV6/CFZ-induced cell death, confirming the cysteinase dependence. XIAP blocked apoptotic execution by inhibiting cysteinase activity, while cIAP1/2 regulated pro-survival nuclear factor kappa B (NF-κB) signaling43. Smac mimicry-induced cIAP depletion leads to the accumulation of NF-κB-inducible kinase (NIK). Tumor necrosis factor (TNF) α, a well-described NF-κB target gene, over binds to cell surface receptors and induces receptor-mediated cell death, further enhancing apoptotic cell death 44.