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A novel small-molecule IAP antagonist, AZD5582, draws Mcl-1 down-regulation for induction of apoptosis through targeting of cIAP1 and XIAP in human pancreatic cancer

Jai-Hee Moon, Jae-Sik Shin, Seung-Woo Hong, Soo-A Jung, Ih-Yeon Hwang, Jeong Hee Kim, Eun Kyoung Choi, Seung-Hee Ha, Jin-Sun Kim, Kyoung-Mok Kim, Dae-Won Hong, Daejin Kim, Yeong Seok Kim, Jeong Eun Kim, Kyu-Pyo Kim, Yong Sang Hong, Eun Kyung Choi, Jung Shin Lee _, Maureen Hattersley, Dong-Hoon Jin and Tae Won Kim

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Oncotarget. 2015; 6:26895-26908. https://doi.org/10.18632/oncotarget.4822

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Abstract

Jai-Hee Moon1,2,*, Jae-Sik Shin1,2,*, Seung-Woo Hong1,2,*, Soo-A Jung1,2, Ih-Yeon Hwang1,2, Jeong Hee Kim1,2, Eun Kyoung Choi1,2, Seung-Hee Ha1,2, Jin-Sun Kim1,5, Kyoung-Mok Kim6, Dae-Won Hong6, Daejin Kim7, Yeong Seok Kim7, Jeong Eun Kim1,2, Kyu-Pyo Kim1,2, Yong Sang Hong1,2, Eun Kyung Choi1,3, Jung Shin Lee1,2, Maureen Hattersley8, Dong-Hoon Jin1,2,4, Tae Won Kim1,2

1Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea

2Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea

3Department of Radiation Oncology, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea

4Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea

5Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea

6University of Ulsan College of Medicine, Seoul, Republic of Korea

7Department of Anatomy, Inje University College of Medicine, Busanjin-ku, Busan, Republic of Korea

8Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, Waltham, Massachusetts, USA

*These authors have contributed equally to this work

Correspondence to:

Dong-Hoon Jin, e-mail: inno183@amc.seoul.kr

Tae Won Kim, e-mail: twkimmd@amc.seoul.kr

Keywords: IAP antagonist, Mcl-1, AZD5582, apoptosis, pancreatic cancer cells

Abbreviations: IAPs, Inhibitor of apoptosis proteins; MEFs, mouse embryonic fibroblasts

Received: January 12, 2015     Accepted: July 24, 2015     Published: August 06, 2015

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.


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