Therapy-induced lipid uptake and remodeling underpin ferroptosis hypersensitivity in prostate cancer
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RESEARCH
Open Access
Therapy-induced lipid uptake and remodeling underpin ferroptosis hypersensitivity in prostate cancer Kaylyn D. Tousignant1†, Anja Rockstroh1, Berwyck L. J. Poad3, Ali Talebi4, Reuben S. E. Young3, Atefeh Taherian Fard1, Rajesh Gupta3, Tuo Zang1, Chenwei Wang1, Melanie L. Lehman1,5, Johan V. Swinnen4, Stephen J. Blanksby3, Colleen C. Nelson1 and Martin C. Sadowski1,2*†
Abstract Background: Metabolic reprograming, non-mutational epigenetic changes, increased cell plasticity, and multidrug tolerance are early hallmarks of therapy resistance in cancer. In this temporary, therapy-tolerant state, cancer cells are highly sensitive to ferroptosis, a form of regulated cell death that is caused by oxidative stress through excess levels of iron-dependent peroxidation of polyunsaturated fatty acids (PUFA). However, mechanisms underpinning therapy-induced ferroptosis hypersensitivity remain to be elucidated. Methods: We used quantitative single-cell imaging of fluorescent metabolic probes, transcriptomics, proteomics, and lipidomics to perform a longitudinal analysis of the adaptive response to androgen receptor-targeted therapies (androgen deprivation and enzalutamide) in prostate cancer (PCa). Results: We discovered that cessation of cell proliferation and a robust reduction in bioenergetic processes were associated with multidrug tolerance and a strong accumulation of lipids. The gain in lipid biomass was fueled by enhanced lipid uptake through cargo non-selective (macropinocytosis, tunneling nanotubes) and cargo-selective mechanisms (lipid transporters), whereas de novo lipid synthesis was strongly reduced. Enzalutamide induced extensive lipid remodeling of all major phospholipid classes at the expense of storage lipids, leading to increased desaturation and acyl chain length of membrane lipids. The rise in membrane PUFA levels enhanced membrane fluidity and lipid peroxidation, causing hypersensitivity to glutathione peroxidase (GPX4) inhibition and ferroptosis. Combination treatments against AR and fatty acid desaturation, lipase activities, or growth medium supplementation with antioxidants or PUFAs altered GPX4 dependence. (Continued on next page)
* Correspondence: [email protected] † Kaylyn D. Tousignant and Martin C. Sadowski contributed equally to this work. 1 Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology (QUT), Princess Alexandra Hospital, Translational Research Institute, Brisbane, Australia 2 Cancer & Ageing Research Program, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology (QUT), Translational Research Institute, Brisbane, Australia Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adapta
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