Rapamycin inhibits Stearoyl-CoA Desaturase 1 expression in breast cancer cell lines.

4353

Stearoyl-CoA Desaturase 1(SCD1) is an enzyme that catalyzes the rate limiting step in the biosynthesis of mono-unsaturated fatty acids. These fatty acids are key components of membrane phospholipids and as a result, affect membrane fluidity and cell division rates. Unbalanced levels are implicated in both increased cell proliferation and carcinogenesis. Here we show that the mammalian target of rapamycin (mTOR) plays a role in SCD1 expression in breast cancer cell lines. To identify novel pharmacodynamic markers of response to rapamycin, we determined genes regulated by rapamycin at the transcriptional or translational level in three rapamycin-sensitive breast cancer cell lines BT474, MCF7 and MDA-MB-468. Cells were treated with rapamycin verses vehicle. Cell lysates were separated on sucrose gradients, and polysomal (translationally active) fractions were subjected to transcriptional profiling. We found that rapamycin treatment was associated with a significant decrease in SCD1 mRNA in the polysomal fractions in all three cell lines. QPCR and northern analysis demonstrate that SCD1 mRNA is decreased not only in polysomal fractions but at the total RNA level as well. Rapamycin treatment led to a decrease in SCD1 protein expression in all three cell lines. Other inhibitors of PI3K/mTOR signaling, notably LY294002 and PI-103, also inhibited SCD1 expression while MAPK inhibitor PD98059 did not. We also showed an up-regulation of SCD1 in the presence of serum, insulin and insulin-like growth factor, all known activators of mTOR signaling. We therefore conclude that SCD1 expression is regulated by rapamycin, suggesting a novel interaction between mTOR signaling and cellular fat metabolism. Further study is needed to determine the role of SCD1 down-regulation in rapamycin-mediated growth inhibition, and SCD1’s role as a potential pharmacodynamic marker of response to mTOR inhibitors.