癌細(xì)胞增殖需要加速的新陳代謝，為了了解癌細(xì)胞對脂肪酸代謝的依賴性,，近日美國健贊公司Kara Carter等人開展了一項有意義的研究,，他們評估了脂肪酸合成通路的各種節(jié)點(diǎn)，發(fā)現(xiàn)抑制一種酶會通過耗盡單一不飽和脂肪酸結(jié)果導(dǎo)致癌癥細(xì)胞死亡,。相關(guān)研究發(fā)表與3月22日的美國《公共科學(xué)圖書館·綜合》（PLoS One）上,。
研究者使用RNAi證明，在HCT116克隆癌細(xì)胞中，消耗脂肪酸合成通路中的酶SCD1, FASN或ACC1會導(dǎo)致細(xì)胞毒性（該毒性可逆,，可以通過加入外源的脂肪酸來逆轉(zhuǎn)）,。當(dāng)耗盡SCD1時，這種條件依賴的表型非常顯著,。研究人員使用脂肪酸救援策略來研究與脂肪酸合成有關(guān)的幾種小分子抑制子,。鑒定發(fā)現(xiàn)TOFA可以作為一個強(qiáng)力的SCD1抑制劑，這說明了這個化合物以前未知的活性,。對比FASN及AC的抑制劑發(fā)現(xiàn),，它們產(chǎn)生的細(xì)胞毒性不如TOFA顯著，采用脂肪酸救援的結(jié)果與之一致,。
兩個參照的SCD1抑制劑表明,，低濃度的細(xì)胞毒性可以被至少兩個數(shù)量級的外源油酸鹽所抵消。該研究概述了通路節(jié)點(diǎn)特異性脂肪酸合成抑制劑,，并在脂肪酸合成以及腫瘤細(xì)胞生長之間建立了清楚的關(guān)系,，也為SCD1作為一個消滅癌細(xì)胞的潛在有效靶點(diǎn)提供了實(shí)驗(yàn)依據(jù)。（生物谷Deepblue編譯）
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.
