Inhibition of fatty acid desaturation is detrimental to cancer cell survival in metabolically compromised environments

BACKGROUND - Enhanced macromolecule biosynthesis is integral to growth and proliferation of cancer cells. Lipid biosynthesis has been predicted to be an essential process in cancer cells. However, it is unclear which enzymes within this pathway offer the best selectivity for cancer cells and could be suitable therapeutic targets.

RESULTS - Using functional genomics, we identified stearoyl-CoA desaturase (SCD), an enzyme that controls synthesis of unsaturated fatty acids, as essential in breast and prostate cancer cells. SCD inhibition altered cellular lipid composition and impeded cell viability in the absence of exogenous lipids. SCD inhibition also altered cardiolipin composition, leading to the release of cytochrome C and induction of apoptosis. Furthermore, SCD was required for the generation of poly-unsaturated lipids in cancer cells grown in spheroid cultures, which resemble those found in tumour tissue. We also found that SCD mRNA and protein expression is elevated in human breast cancers and predicts poor survival in high-grade tumours. Finally, silencing of SCD in prostate orthografts efficiently blocked tumour growth and significantly increased animal survival.

CONCLUSIONS - Our data implicate lipid desaturation as an essential process for cancer cell survival and suggest that targeting SCD could efficiently limit tumour expansion, especially under the metabolically compromised conditions of the tumour microenvironment.

Cancer & metabolism. 2016 Apr 01*** epublish ***

Barrie Peck, Zachary T Schug, Qifeng Zhang, Beatrice Dankworth, Dylan T Jones, Elizabeth Smethurst, Rachana Patel, Susan Mason, Ming Jiang, Rebecca Saunders, Michael Howell, Richard Mitter, Bradley Spencer-Dene, Gordon Stamp, Lynn McGarry, Daniel James, Emma Shanks, Eric O Aboagye, Susan E Critchlow, Hing Y Leung, Adrian L Harris, Michael J O Wakelam, Eyal Gottlieb, Almut Schulze

Gene Expression Analysis Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3LY UK ; Present address: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB UK., Cancer Research UK, Beatson Institute, Switchback Rd, Glasgow, G61 1BD UK., Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT UK., Department for Biochemistry and Molecular Biology, Theodor-Boveri-Institute, University of Würzburg, Am Hubland, 97074 Würzburg, Germany., Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS UK., Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT UK., Cancer Research UK, Beatson Institute, Switchback Rd, Glasgow, G61 1BD UK., Cancer Research UK, Beatson Institute, Switchback Rd, Glasgow, G61 1BD UK., High Throughput Screening Facility, The Francis Crick Institute, Lincoln`s Inn Fields Laboratories, 44 Lincoln`s Inn Fields, London, WC2A 3LY UK., High Throughput Screening Facility, The Francis Crick Institute, Lincoln`s Inn Fields Laboratories, 44 Lincoln`s Inn Fields, London, WC2A 3LY UK., High Throughput Screening Facility, The Francis Crick Institute, Lincoln`s Inn Fields Laboratories, 44 Lincoln`s Inn Fields, London, WC2A 3LY UK., Bioinformatics and Biostatistics Service, The Francis Crick Institute, Lincoln`s Inn Fields Laboratories, 44 Lincoln`s Inn Fields, London, WC2A 3LY UK., Experimental Histopathology, The Francis Crick Institute, Lincoln`s Inn Fields Laboratories, 44 Lincoln`s Inn Fields, London, WC2A 3LY UK., Experimental Histopathology, The Francis Crick Institute, Lincoln`s Inn Fields Laboratories, 44 Lincoln`s Inn Fields, London, WC2A 3LY UK., Cancer Research UK, Beatson Institute, Switchback Rd, Glasgow, G61 1BD UK., Cancer Research UK, Beatson Institute, Switchback Rd, Glasgow, G61 1BD UK., Cancer Research UK, Beatson Institute, Switchback Rd, Glasgow, G61 1BD UK., Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN UK., AstraZeneca, Mereside, Alderley Park, Macclesfield, SK10 4TG UK., Cancer Research UK, Beatson Institute, Switchback Rd, Glasgow, G61 1BD UK., Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS UK., Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT UK., Cancer Research UK, Beatson Institute, Switchback Rd, Glasgow, G61 1BD UK., Gene Expression Analysis Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3LY UK ; Department for Biochemistry and Molecular Biology, Theodor-Boveri-Institute, University of Würzburg, Am Hubland, 97074 Würzburg, Germany ; Comprehensive Cancer Center Mainfranken, Josef-Schneider-Str. 6, 97080 Würzburg, Germany.

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