Enhanced lipid uptake and lipid remodelling are adaptive responses to androgen-targeted therapies in prostate cancer

Wiley-Blackwell Publishing Ltd 2018-08

Objective: Current mainstay treatments of advanced prostate cancer (PCa) target the androgen receptor (AR), a transcription factor that controls the expression of a large gene set associated with metabolism, differentiation, survival and tumour growth. Despite initial disease regression following AR-targeted therapies (ATTs) through androgen deprivation therapy or AR antagonist therapy, almost all patients with advanced PCa progress to incurable castrate-resistant PCa (CRPC). We hypothesise that adaptive responses to ATTs are critical for CRPC development and that identifying and targeting these responses may delay disease progression. Methods: We developed long-term ATT models of PCa cells and used cutting-edge technologies like quantitative fluorescent microscopy, lipid and protein mass spectrometry, 13C metabolomics, DNA microarray, Seahorse fuel-flex assay and real-time cell confluence imaging to measure adaptive changes to lipid metabolism (uptake, synthesis and content), the proteome and transcriptome, mitochondrial activity and proliferation over the 21 day treatment course. Results: ATTs strongly suppressed growth by arresting cells in G0/G1, lowered ATP levels and only modestly increased cell death. Surprisingly, cell quiescence was associated with increased lipid content, and enhanced lipid uptake of cholesterol and low density lipoprotein. Lipidomics revealed extensive lipid remodelling, including a decrease in lipid storage (triacylglycerols and cholesterol esters) and increase in essential fatty acids, phospholipids and sphingomyelin as well as elongation and desaturation of fatty acids. Finally, lipid transporters and phospholipases were identified and characterised as targets against the adaptive response to ATTs. Conclusions: Targeting enhanced lipid uptake and remodelling are novel therapeutic strategies to delay the progression to CRPC.

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2018 The Authors & BJU International
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Institute of Health and Biomedical Innovation; Institute for Future Environments; Science & Engineering Faculty; School of Chemistry, Physics & Mechanical Engineering
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QUEENSLAND UNIV OF TECH
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