Genzyme Corporation, Waltham, Massachusetts, United States of America.
PLoS One. 2012;7(3):e33823. doi: 10.1371/journal.pone.0033823. Epub 2012 Mar 22.
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.
新陈代谢增加是肿瘤细胞增殖的要求。为了了解肿瘤细胞对脂肪酸代谢的依赖性，我们评估了脂肪酸合成途径的各种节点。通过 RNAi，我们已经证明，在 HCT116 结肠癌细胞中耗尽脂肪酸合成途径酶 SCD1、FASN 或 ACC1 会导致细胞毒性，而外源性脂肪酸的添加可使其逆转。当 SCD1 耗尽时，这种条件表型最为明显。我们使用这种脂肪酸挽救策略来表征几种脂肪酸合成的小分子抑制剂，包括鉴定 TOFA 作为一种有效的 SCD1 抑制剂，这代表了该化合物以前未描述的活性。参考 FASN 和 ACC 抑制剂的细胞毒性不如 TOFA 明显，并且脂肪酸挽救谱与其提议的酶靶标一致。两种参考 SCD1 抑制剂显示出低纳摩尔的细胞毒性，但至少被外源性油酸抵消了两个数量级。其中一种抑制剂可减缓 HCT116 异种移植肿瘤的生长。我们的数据概述了一种有效的策略，可以研究脂肪酸合成抑制剂的作用机制效力和途径节点特异性，在脂肪酸合成与癌细胞存活之间建立明确的联系，并将 SCD1 确定为该途径中的关键靶标。
