1. Chemosensitivity to HM90822, a novel synthetic IAP antagonist, is determined by p-AKT-inducible XIAP phosphorylation in human pancreatic cancer cells
- Author
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Jung Shin Lee, Jun Ki Hong, Eun Ho Kim, Do Yeon Kim, Yeaseong Ryu, Kwee Hyun Suh, Seung-Woo Hong, Jai-Hee Moon, Ig-Jun Cho, Sangsoo Park, In Hwan Bae, Young-Gil Ahn, Jong Soon Kang, Hong-Rae Jeong, Dong-In Koh, Yong Sang Hong, Tae Won Kim, Yoon Sun Park, Mi Jin Kim, Soo-A Jung, Dong-Hoon Jin, and Jae-Sik Shin
- Subjects
0301 basic medicine ,Mice, Nude ,Antineoplastic Agents ,Inhibitor of apoptosis ,Inhibitor of Apoptosis Proteins ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Pancreatic cancer ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Phosphorylation ,Protein kinase B ,Caspase ,Pharmacology ,Mice, Inbred BALB C ,biology ,Chemistry ,Ubiquitination ,medicine.disease ,Tumor Burden ,XIAP ,Pancreatic Neoplasms ,030104 developmental biology ,Oncology ,Proteasome ,Drug Resistance, Neoplasm ,Apoptosis ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Female ,Proto-Oncogene Proteins c-akt - Abstract
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.
- Published
- 2020