Brusselmans Koen, De Schrijver Ellen, Verhoeven Guido, Swinnen Johannes V
Laboratory for Experimental Medicine and Endocrinology, University of Leuven, Leuven, Belgium.
Cancer Res. 2005 Aug 1;65(15):6719-25. doi: 10.1158/0008-5472.CAN-05-0571.
Overexpression of lipogenic enzymes is a common characteristic of many cancers. Thus far, studies aimed at the exploration of lipogenic enzymes as targets for cancer intervention have focused on fatty acid synthase (FAS), the enzyme catalyzing the terminal steps in fatty acid synthesis. Chemical inhibition or RNA interference (RNAi)-mediated knockdown of FAS consistently inhibits the growth and induces death of cancer cells. Accumulation of the FAS substrate malonyl-CoA has been implicated in the mechanism of cytotoxicity of FAS inhibition. Here, using RNAi technology, we have knocked down the expression of acetyl-CoA carboxylase-alpha (ACC-alpha), the enzyme providing the malonyl-CoA substrate. Silencing of the ACC-alpha gene resulted in a similar inhibition of cell proliferation and induction of caspase-mediated apoptosis of highly lipogenic LNCaP prostate cancer cells as observed after FAS RNAi. In nonmalignant cells with low lipogenic activity, no cytotoxic effects of knockdown of ACC-alpha or FAS were observed. These findings indicate that accumulation of malonyl-CoA is not a prerequisite for cytotoxicity induced by inhibition of tumor-associated lipogenesis and suggest that in addition to FAS, ACC-alpha is a potential target for cancer intervention.
脂肪生成酶的过表达是许多癌症的共同特征。到目前为止，旨在探索将脂肪生成酶作为癌症干预靶点的研究主要集中在脂肪酸合酶（FAS）上，该酶催化脂肪酸合成的最后几步。化学抑制或RNA干扰（RNAi）介导的FAS敲低持续抑制癌细胞的生长并诱导其死亡。FAS底物丙二酰辅酶A的积累与FAS抑制的细胞毒性机制有关。在这里，我们使用RNAi技术敲低了提供丙二酰辅酶A底物的乙酰辅酶A羧化酶α（ACC-α）的表达。ACC-α基因的沉默导致与FAS RNAi后观察到的高度脂肪生成的LNCaP前列腺癌细胞的细胞增殖抑制和半胱天冬酶介导的凋亡诱导相似。在脂肪生成活性低的非恶性细胞中，未观察到ACC-α或FAS敲低的细胞毒性作用。这些发现表明丙二酰辅酶A的积累不是抑制肿瘤相关脂肪生成诱导细胞毒性的先决条件，并表明除FAS外，ACC-α也是癌症干预的潜在靶点。
