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Chemosensitivity to HM90822, a novel synthetic IAP antagonist, is determined by p-AKT-inducible XIAP phosphorylation in human pancreatic cancer cells
- Source :
- Investigational New Drugs. 38:1696-1706
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
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.
- 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
Subjects
Details
- ISSN :
- 15730646 and 01676997
- Volume :
- 38
- Database :
- OpenAIRE
- Journal :
- Investigational New Drugs
- Accession number :
- edsair.doi.dedup.....68c09df164e5ed9bd2d42f0dc4697713