Chemosensitivity to HM90822, a novel synthetic IAP antagonist, is determined by p-AKT-inducible XIAP phosphorylation in
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PRECLINICAL STUDIES
Chemosensitivity to HM90822, a novel synthetic IAP antagonist, is determined by p-AKT-inducible XIAP phosphorylation in human pancreatic cancer cells Seung-Woo Hong 1,2,3 & Jae-Sik Shin 1,2,3 & Jai-Hee Moon 1,2,4 & Soo-A Jung 1,2,4 & Dong-In Koh 2,3 & Yeaseong Ryu 2,4 & Yoon Sun Park 2,4 & Do Yeon Kim 2,4 & Sang-Soo Park 2,4 & Jun Ki Hong 2,4 & Eun Ho Kim 2,4 & Mi Jin Kim 2,4 & Hong-Rae Jeong 2,4 & In Hwan Bae 5 & Young-Gil Ahn 5 & Kwee Hyun Suh 5 & Ig-Jun Cho 6 & Jong-Soon Kang 7 & Yong Sang Hong 1,8 & Jung Shin Lee 1,8 & Dong-Hoon Jin 1,2,4,9 & Tae Won Kim 1,8 Received: 7 March 2020 / Accepted: 21 May 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Summary Inhibitor of apoptosis proteins (IAPs) are overexpressed in the majority of cancers and prevent apoptosis by inhibiting caspases. IAPs have therefore attracted considerable attention as potential targets for anticancer therapy. Here, we demonstrated that HM90822 (abbreviated HM822; a new synthetic IAP antagonist) induced apoptotic cell death via proteasome-dependent degradation of BIR2/3 domain-containing IAPs in human pancreatic cancer cells. HM822 inhibited the expression of XIAP and cIAP1/2 proteins in Panc-1 and BxPC-3 cells, which are sensitive to HM822. HM822 also induced IAP ubiquitination and promoted proteasome-dependent IAP degradation. However, cells expressing phospho-XIAP (Ser87) and AKT exhibited resistance to HM822. In other words, the overexpression of AKT-CA (constitutive active form for AKT) or AKT-WT induced resistance to HM822. In addition, in Panc-1 xenograft and orthotopic mouse models, we revealed that tumor growth was suppressed by the administration of HM822. Taken together, these results suggest that HM822 induces apoptosis through ubiquitin/proteasome-dependent degradation of BIR3 domain-containing IAPs. These findings suggest that phospho-XIAP and phospho-AKT may be used as biomarkers for predicting the efficacy of HM822 in pancreatic cancer patients. Keywords IAPs . HM90822 (HM822) . ubiquitination . apoptosis . pancreatic cancer
Seung-Woo Hong, Jae-Sik Shin and Jai-Hee Moon contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10637-020-00956-9) contains supplementary material, which is available to authorized users. * Dong-Hoon Jin [email protected] * Tae Won Kim [email protected] 1
2
Institute for Innovative Cancer Research, Asan Medical Center, Seoul, Republic of Korea Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
3
Department of Convergence Medicine, Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
4
Department of Medical Science, Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
5
Hanmi Research Center, Hanmi Pharm. Co., Ltd, Gyeonggi-do, Republic of Korea
6
Osong Medical Innovation Foundation, Cheongju-si, Republic of Korea
7
Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Och
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