Emerging literature suggests that metabolic pathways play an important role in the maintenance and progression of human
cancers. In particular, recent studies have implicated
lipid biosynthesis and desaturation as a requirement for
tumor cell survival. In the studies reported here, we aimed to understand whether
tumor cells require the activity of either human
isoform of
stearoyl-CoA-desaturase (SCD1 or SCD5) for survival. Inhibition of SCD1 by
siRNA or a small molecule antagonist results in strong induction of apoptosis and growth inhibition, when
tumor cells are cultured in reduced (2%) serum conditions, but has little impact on cells cultured in 10% serum. Depletion of SCD5 had minimal effects on cell growth or apoptosis. Consistent with the observed dependence on SCD1, but not SCD5, levels of SCD1
protein increased in response to decreasing serum levels. Both induction of SCD1
protein and sensitivity to growth inhibition by SCD1 inhibition could be reversed by supplementing growth media with
unsaturated fatty acids, the product of the enzymatic reaction catalyzed by SCD1. Transcription profiling of cells treated with an SCD inhibitor revealed strong induction of markers of endoplasmic reticulum stress. Underscoring its importance in
cancer, SCD1
protein was found to be highly expressed in a large percentage of human
cancer specimens. SCD inhibition resulted in
tumor growth delay in a human
gastric cancer xenograft model. Altogether, these results suggest that desaturated
fatty acids are required for
tumor cell survival and that SCD may represent a viable target for the development of novel agents for
cancer therapy.