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

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

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.