Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/25025
Title: Secreted cellular prion protein binds doxorubicin and correlates with anthracycline resistance in breast cancer.
Austin Authors: Wiegmans, Adrian P;Saunus, Jodi M;Ham, Sunyoung;Lobb, Richard;Kutasovic, Jamie R;Dalley, Andrew J;Miranda, Mariska;Atkinson, Caroline;Foliaki, Simote T;Ferguson, Kaltin;Niland, Colleen;Johnstone, Cameron N ;Lewis, Victoria;Collins, Steven J;Lakhani, Sunil R;Al-Ejeh, Fares;Möller, Andreas
Affiliation: Tumor Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Parkville, Victoria, Australia
Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Herston, Queensland, Australia
Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales, Australia
Personalized Medicine Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
Olivia Newton-John Cancer Research Institute
Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Parkville, Victoria, Australia
Issue Date: 26-Feb-2019
Date: 2019
Publication information: JCI Insight 2019; 5(6): e124092
Abstract: Anthracyclines are amongst the most effective chemotherapeutics ever developed, but they produce grueling side-effects, serious adverse events and resistance often develops over time. We found that these compounds can be sequestered by secreted cellular Prion protein (PrPC), blocking their cytotoxic activity. This effect was dose-dependent using either cell line-conditioned medium or human serum as a source of PrPC. Genetic depletion of PrPC or inhibition of binding via chelation of ionic copper prevented the interaction and restored cytotoxic activity. This was more pronounced for doxorubicin than its epimer, epirubicin. Investigating the relevance to breast cancer management, we found that the levels of PRNP transcript in pre-treatment tumor biopsies stratified relapse-free survival after neoadjuvant treatment with anthracyclines, particularly amongst doxorubicin-treated patients with residual disease at surgery (p=2.8E-08). These data suggest that local sequestration could mediate treatment resistance. Consistent with this, tumor cell expression of PrPC protein correlated with poorer response to doxorubicin but not epirubicin in an independent cohort analyzed by immunohistochemistry, particularly soluble isoforms released into the extracellular environment by shedding (p=0.015). These findings have important potential clinical implications for frontline regimen decision-making. We suggest there is warranted utility for prognostic PrPC/PRNP assays to guide chemo-sensitization strategies that exploit an understanding of PrPC-anthracycline-copper ion complexes.
URI: https://ahro.austin.org.au/austinjspui/handle/1/25025
DOI: 10.1172/jci.insight.124092
Journal: JCI Insight
PubMed URL: 30830863
Type: Journal Article
Subjects: Cell Biology
Oncology
Prions
Appears in Collections:Journal articles

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