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

Title: Inhibition of fatty acid desaturation is detrimental to cancer cell survival in metabolically compromised environments
Authors: Peck, B
Schug, ZT
Zhang, Q
Dankworth, B
Jones, DT
Smethurst, E
Patel, R
Mason, S
Jiang, M
Saunders, R
Howell, M
Mitter, R
Spencer-Dene, B
Stamp, G
McGarry, L
James, D
Shanks, E
Aboagye, EO
Critchlow, SE
Leung, HY
Harris, AL
Wakelam, MJ
Gottlieb, E
Schulze, A
Item Type: Journal Article
Abstract: 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.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.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.
Issue Date: 1-Apr-2016
Date of Acceptance: 7-Mar-2016
URI: http://hdl.handle.net/10044/1/31783
DOI: http://dx.doi.org/10.1186/s40170-016-0146-8
ISSN: 2049-3002
Publisher: BioMed Central
Journal / Book Title: Cancer and Metabolism
Volume: 4
Copyright Statement: © 2016 Peck et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Sponsor/Funder: Cancer Research UK
Funder's Grant Number: WSCC_P34611
Keywords: Breast cancer
Lipid desaturation
Lipidomics
Prostate cancer
SCD
Publication Status: Published
Article Number: 6
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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