癌细胞增殖需要加速的新陈代谢，为了了解癌细胞对脂肪酸代谢的依赖性，近日美国健赞公司Kara Carter等人开展了一项有意义的研究，他们评估了脂肪酸合成通路的各种节点，发现抑制一种酶会通过耗尽单一不饱和脂肪酸结果导致癌症细胞死亡。相关研究发表与3月22日的美国《公共科学图书馆·综合》（PLoS One）上。
研究者使用RNAi证明，在HCT116克隆癌细胞中，消耗脂肪酸合成通路中的酶SCD1, FASN或ACC1会导致细胞毒性（该毒性可逆，可以通过加入外源的脂肪酸来逆转）。当耗尽SCD1时，这种条件依赖的表型非常显著。研究人员使用脂肪酸救援策略来研究与脂肪酸合成有关的几种小分子抑制子。鉴定发现TOFA可以作为一个强力的SCD1抑制剂，这说明了这个化合物以前未知的活性。对比FASN及AC的抑制剂发现，它们产生的细胞毒性不如TOFA显著，采用脂肪酸救援的结果与之一致。
两个参照的SCD1抑制剂表明，低浓度的细胞毒性可以被至少两个数量级的外源油酸盐所抵消。该研究概述了通路节点特异性脂肪酸合成抑制剂，并在脂肪酸合成以及肿瘤细胞生长之间建立了清楚的关系，也为SCD1作为一个消灭癌细胞的潜在有效靶点提供了实验依据。（生物谷Deepblue编译）
doi: 10.1371/journal.pone.0033823
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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.
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.
