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.