SCD1 Inhibition Causes Cancer Cell Death by Depleting Mono-Unsaturated Fatty Acids

Abstract

Increased metabolism is a requirement for tumor cell proliferation. To understand the dependence of tumor cells on fatty acid metabolism, we evaluated various nodes of the fatty acid synthesis pathway. Using RNAi we have demonstrated that depletion of fatty-acid synthesis pathway enzymes SCD1, FASN, or ACC1 in HCT116 colon cancer cells results in cytotoxicity that is reversible by addition of exogenous fatty acids. This conditional phenotype is most pronounced when SCD1 is depleted. We used this fatty-acid rescue strategy to characterize several small-molecule inhibitors of fatty acid synthesis, including identification of TOFA as a potent SCD1 inhibitor, representing a previously undescribed activity for this compound. Reference FASN and ACC inhibitors show cytotoxicity that is less pronounced than that of TOFA, and fatty-acid rescue profiles consistent with their proposed enzyme targets. Two reference SCD1 inhibitors show low-nanomolar cytotoxicity that is offset by at least two orders of magnitude by exogenous oleate. One of these inhibitors slows growth of HCT116 xenograft tumors. Our data outline an effective strategy for interrogation of on-mechanism potency and pathway-node-specificity of fatty acid synthesis inhibitors, establish an unambiguous link between fatty acid synthesis and cancer cell survival, and point toward SCD1 as a key target in this pathway.

IRE1α RNase–dependent lipid homeostasis promotes survival in Myc-transformed cancers

“…SCDi administration significantly decreased tumor growth and tumor weight ( Figure 6F). However, this was also accompanied by a slight weight loss during treatment (Supplemental Figure 6E), as observed in a previous study (42). Finally, SCDi treatment engaged all 3 UPR pathways (ATF6: HERPUD1; IRE1: XBP1s, DNAJB9; PERK: ATF3, DDIT3), and each was reversed with OA supplementation (Supplemental Figure 6F).…”

Drug Redeployment to Kill Leukemia and Lymphoma Cells by Disrupting SCD1-Mediated Synthesis of Monounsaturated Fatty Acids

“…Inhibition of these enzymes has been demonstrated to be selectively toxic to some cancer cells in vitro (18,(20)(21)(22)(23)(24), suggesting that this pathway might represent a good target for anticancer drugs. In particular, cancer cells appear to have a high dependence on monounsaturated fatty acids (39), which are key components of phospholipids. Monounsaturated fatty acids can also protect cells against saturated fatty acid toxicity by enhancing safe storage of saturates into TAGs (25,26).…”

“…Monounsaturated fatty acids have been shown to be important in cancer (39,45), which, in part, is due to their requirement for cellular growth and proliferation. SCD1 is suggested be a major driver of fatty acid synthesis from glucose (46) and has also been shown to help negotiate cellular stress, with SCD1 inhibition leading to saturated fatty acid accumulation, toxicity, and endoplasmic reticulum stress (40,47,48).…”

Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids

“…A specific ratio of oleate to stearate must be maintained by cells to ensure proper membrane fluidity and thus cell integrity, and a significant imbalance has been shown to induce apoptosis (13)(14)(15). SCD1 is regulated by the PI3K-Akt-mTOR pathway (5) and has been investigated as a pharmacological target for both obesity and cancer (16)(17)(18)(19).…”