scd1 inhibition causes cancer cell death by depleting mono-unsaturated fatty acidsscd1抑制致癌细胞死亡的消耗单不饱和脂肪酸.pdfVIP

SCD1 Inhibition Causes Cancer Cell Death by Depleting Mono-Unsaturated Fatty Acids Paul Mason*, Beirong Liang, Lingyun Li, Trisha Fremgen, Erin Murphy, Angela Quinn, Stephen L. Madden, Hans-Peter Biemann, Bing Wang, Aharon Cohen, Svetlana Komarnitsky, Kate Jancsics, Brad Hirth, Christopher G. F. Cooper, Edward Lee, Sean Wilson, Roy Krumbholz, Steven Schmid, Yibin Xiang, Michael Booker, James Lillie, Kara Carter Genzyme Corporation, Waltham, Massachusetts, United States of America 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, an