Knowles Lynn M, Yang Chen, Osterman Andrei, Smith Jeffrey W
Cancer Research Center, Burham Institute for Medical Research, La Jolla, California 92037, USA.
J Biol Chem. 2008 Nov 14;283(46):31378-84. doi: 10.1074/jbc.M803384200. Epub 2008 Sep 16.
Fatty-acid synthase (FAS) is up-regulated in a broad range of cancers, including those of the breast, prostate, and ovaries. In tumor cells, the inhibition of FAS elicits cell cycle arrest and apoptosis, so it is considered a potential drug target for oncology. Results from this study show that inhibition of FAS, by either knockdown with small interfering RNA or inhibition with the small molecule drug orlistat, leads to activation of the receptor-mediated apoptotic cascade (caspase-8-mediated) and ultimately to cell death. However, knockdown of two enzymes upstream of FAS, acetyl-CoA carboxylase-alpha and ATP-citrate lyase, fails to activate caspase-8 or to elicit apoptosis in tumor cells, even though palmitate synthesis was suppressed. Using differential gene analysis, we traced the unique apoptotic effect of FAS inhibition to up-regulation of DDIT4 (DNA damage-inducible transcript 4), a stress-response gene that negatively regulates the mTOR pathway. These findings indicate that suppression of palmitate synthesis is not sufficient for eliciting tumor cell death and suggest that the unique effect of inhibition of FAS results from negative regulation of the mTOR pathway via DDIT4.
脂肪酸合酶（FAS）在包括乳腺癌、前列腺癌和卵巢癌在内的多种癌症中上调。在肿瘤细胞中，抑制FAS会引发细胞周期停滞和凋亡，因此它被认为是肿瘤学的一个潜在药物靶点。这项研究的结果表明，通过小分子干扰RNA敲低或小分子药物奥利司他抑制FAS，会导致受体介导的凋亡级联反应（半胱天冬酶-8介导）的激活，并最终导致细胞死亡。然而，FAS上游的两种酶，即乙酰辅酶A羧化酶-α和ATP-柠檬酸裂解酶的敲低，即使抑制了棕榈酸的合成，也无法激活半胱天冬酶-8或引发肿瘤细胞凋亡。通过差异基因分析，我们将FAS抑制的独特凋亡效应追溯到DDIT4（DNA损伤诱导转录本4）的上调，DDIT4是一个负调节mTOR途径的应激反应基因。这些发现表明，抑制棕榈酸合成不足以引发肿瘤细胞死亡，并提示抑制FAS的独特效应源于通过DDIT4对mTOR途径的负调节。
