The Balance between Saturated and Unsaturated Fatty Acids Regulates Ovarian Cancer Cell Fate

Abstract

AbstractFatty acids are an important source of energy and a key component of phospholipids in membranes and organelles. Saturated (SFAs) are converted into unsaturated fatty acids (UFAs) by stearoyl Co-A desaturase (SCD), an enzyme highly active in cancer. Here we studied how the balance between SFAs and UFAs maintained by SCD impacts cancer cell survival and tumor progression. SCD depletion or inhibition caused lower levels of UFAs vs. SFAs and altered fatty acyl chain plasticity, as demonstrated by lipidomics and stimulated Raman spectroscopy (SRS). Further, the loss of equilibrium between UFAs and SFAs resulting from SCD knock down triggered endoplasmic reticulum (ER) stress response with brisk activation of IRE1α/XBP1 and PERK/eIF2α/ATF4 axes. Stiff and disorganized ER membrane was visualized by electron microscopy and SRS imaging in cells in which SCD was knocked down. The induction of long-term mild ER stress or short-time severe ER stress by the increased levels of SFAs and loss of UFAs led to cell death. However, ER stress and apoptosis could be readily rescued by supplementation with UFAs and re-equilibration of SFA/UFA levels. The effects of SCD knockdown or inhibition observed in vitro, translated into suppression of intraperitoneal tumor growth in xenograft models. Furthermore, a combined intervention using an SCD inhibitor and an SFA enriched diet, initiated ER stress in tumors growing in vivo and potently blocked their dissemination. In all, our data support SCD as a key regulator of the cancer cell fate under metabolic stress and point to new treatment strategies targeting the lipid balance.Significance StatementWe show that the balance between saturated and unsaturated fatty acids tightly regulated by the desaturase SCD impacts the survival of cancer cells; increased levels of unsaturation being protective against ER stress induced apoptosis. Decreasing fatty acid unsaturation, either through SCD depletion or through SCD inhibition coupled with a dietary intervention blocks tumor progression in vivo. Our findings support the concept of targeting the lipid balance as a new target in cancer.