Abstract 592: Novel IAP antagonist (822B) induces apoptosis through degradation of IAP proteins which have a BIR3 domain in human pancreatic cancer cells

Abstract

Abstract Several companies recently began to develop inhibitor of apoptosis (IAP) antagonist ‘Smac/Diablo mimetic’ compounds for the treatment of cancer. IAP antagonist compounds (IACs) was, therefore, designated as being able to induce apoptosis through the inhibition of IAP proteins in cancer cells. In our study we demonstrated that the novel-in what sense is it synthetic IAP antagonist, 822B, induces apoptotic cell death through proteasomal-dependent degradation of the inhibitor of apoptosis proteins (IAPs) with a BIR3 domain. We first found that apoptotic cell death is induced by exposure of pancreatic cancer cells to 822B. This apoptotic effect increased after the knockdown of endogenous IAPs using RNA interference. Moreover, 822B-induced apoptosis results from degradation of the inhibitor of apoptosis proteins (IAPs). 822B was preferable to Samc/Diablo for binding to IAPs and it induced ubiquitination. However, we also found that degradation of XIAP is not induced in several pancreatic cancer cell types in response to 822B. Interestingly, resistance to 822B was related to phosphorylation at the ser-87 site of XIAP. This resistant effect was eliminated using the (or “an” if there's more than one . . .) XIAP mutant that was replaced with alanine at 87 amino acid site. AKT CA (constitutive active) mutant and wild type-AKT that can induce phosphorylation at the ser-87 site of XIAP also suppressed the resistant effect to 822B. In addition, mutation in the RING domain of XIAP was not observed. Mutation in the RING domain of XIAP cannot induce XIAP ubiquitination, thus suggesting that the level of phospho-XIAP and phospho-AKT may be used as an indicator for cancer therapy using 822B. These results suggest that a novel synthetic inhibitor of the apoptosis (IAP) antagonist induces apoptosis through ubiquitination of IAPs with a BIR3 domain. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 592. doi:10.1158/1538-7445.AM2011-592