Abstract
Inhibitor of apoptosis proteins (IAPs) plays an important role in controlling cancer cell survival. IAPs have therefore attracted considerable attention as potential targets in anticancer therapy. In this study, we investigated the anti-tumor effect of AZD5582, a novel small-molecule IAP inhibitor, in human pancreatic cancer cells. Treating human pancreatic cancer cells with AZD5582 differentially induced apoptosis, dependent on the expression of p-Akt and p-XIAP. Moreover, the knockdown of endogenous Akt or XIAP via RNA interference in pancreatic cancer cells, which are resistant to AZD5582, resulted in increased sensitivity to AZD5582, whereas ectopically expressing Akt or XIAP led to resistance to AZD5582. Additionally, AZD5582 targeted cIAP1 to induce TNF-α-induced apoptosis. More importantly, AZD5582 induced a decrease of Mcl-1 protein, a member of the Bcl-2 family, but not that of Bcl-2 and Bcl-xL. Interestingly, ectopically expressing XIAP and cIAP1 inhibited the AZD5582-induced decrease of Mcl-1 protein, which suggests that AZD5582 elicits Mcl-1 decrease for apoptosis induction by targeting of XIAP and cIAP1. Taken together, these results indicate that sensitivity to AZD5582 is determined by p-Akt-inducible XIAP phosphorylation and by targeting cIAP1. Furthermore, Mcl-1 in pancreatic cancer may act as a potent marker to analyze the therapeutic effects of AZD5582.
Highlights
The mortality rate of pancreatic carcinomas, which have a 5-year survival rate of less than 5%, is among the highest of all human cancer types [1]
To validate the effect of AZD5582, we first examined its inhibitory effect on multiple human pancreatic cancer cell lines as a single agent
We examined the inhibitory effect of AZD5582 on BxPC-3 and Panc-1 cells that were sensitive to AZD5582
Summary
The mortality rate of pancreatic carcinomas, which have a 5-year survival rate of less than 5%, is among the highest of all human cancer types [1]. Resistance of pancreatic cancers to even aggressive treatment regimens presents a major challenge in oncology. Previous studies in pancreatic cancer have described multiple defects in apoptosis signaling at different levels of the pathway [2]. Pancreatic cancer cells gain protection against the mitochondrial-dependent apoptotic pathway through overexpression of inhibitor of apoptosis proteins (IAPs), which are inhibitors of caspases [3], as well as through dysregulation of other apoptosismodulating genes [4]. Understanding these mechanisms, which might have great potential as targets for overcoming therapy-resistance of human pancreatic cancer, has opened novel strategies for anticancer drug development
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