Loss of Stearoyl‐CoA Desaturase activity increases ER stress and PKCζ mediated inhibition of Akt in response to saturated fatty acids in breast cancer cells.

Abstract

Increased de novo lipogenesis is a hallmark of invasive tumors and is negatively correlated with survival. However, the end product is the saturated fatty acid (SFA) palmitate that is lipotoxic unless desaturated. Stearoyl‐CoA desaturase (SCD) converts SFA into monounsaturated fatty acids and is the rate limiting step in the storage of triglycerides and the generation of phospholipids. We demonstrate that SCD increases proliferation in HeLa cells in the presence of Cerulenin or exogenous SFA and that stearate decreased cell viability in a dose dependent fashion. While the product of SCD (oleate) can activate Akt, substrate (stearate or palmitate) treatment of cells exhibited a dose dependent increase in PARP cleavage and PKC? expression. We further probed the role of SCD‐1 in WT and SCD‐1 knockout MEFs and established that SFA prevents Akt translocation to lipid rafts. In the presence of a small molecule SCD‐1 inhibitor, palmitate treatment induced ER stress as evidenced by Xbp‐1 splicing. Density gradient analysis and IP experiments of palmitate treated cells showed a decrease in both PKC? and Akt lipid raft localization and an increase in TLR4/IKKβ complex formation. Finally, in transgenic MMTV‐PyMT mice, SCD‐1 deficiency reduced invasiveness of mammary gland tumors. Therefore, we conclude that SCD regulates MUFA mediated proliferation, prevents ER stress, and reduces tumor invasion.