Journal article
Secreted cellular prion protein binds doxorubicin and correlates with anthracycline resistance in breast cancer
AP Wiegmans, JM Saunus, S Ham, R Lobb, JR Kutasovic, AJ Dalley, M Miranda, C Atkinson, ST Foliaki, K Ferguson, C Niland, CN Johnstone, V Lewis, SJ Collins, SR Lakhani, F Al-Ejeh, A Möller
Jci Insight | AMER SOC CLINICAL INVESTIGATION INC | Published : 2019
Abstract
Anthracyclines are among the most effective chemotherapeutics ever developed, but they produce grueling side effects and serious adverse events, and resistance often develops over time. We found that these compounds can be sequestered by secreted cellular prion protein (PrPC), which blocks 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 foun..
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Awarded by Australian National Health & Medical Research Council
Funding Acknowledgements
We would like to thank Parmjit Jat, Iryna Benilova, and Simon Mead (UCL Institute of Prion Diseases) for critical review and feedback on this manuscript. We thank Jason Lee, QIMR Berghofer Medical Research Institute, for his help with data analysis, revision, and formatting. We also acknowledge the Brisbane Breast Bank for clinical samples for IHC and ELISA studies. This study makes use of data generated by the Molecular Taxonomy of Breast Cancer International Consortium (Metabric). This study was supported by funding from Australian National Health & Medical Research Council project grants (APP1068510 to AM and APP1113867 and APP1017028 to SRL) and the Practitioner Fellowship (APP1105784 to SJC).