Acetyl-CoA carboxylase α is essential to breast cancer cell survival
Acetyl-CoA carboxylase α is essential to breast cancer cell survival
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DOI：
10.1158/0008-5472.can-05-1489
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发表时间：
2006-05-15
期刊：
影响因子：
11.2
通讯作者：
Joulin, Virginie
中科院分区：
文献类型：
--
作者：
Chajes, Veronique;Cambot, Marie;Joulin, Virginie
脂肪酸从头合成的激活是癌细胞的一个特征。我们最近描述了乙酰辅酶A羧化酶α（ACCα）（脂肪酸合成中的关键酶）与BRCA1之间的相互作用，这表明脂质合成与乳腺癌和卵巢癌易感性遗传因素之间可能存在联系。为此，我们使用 RNA 干扰 (RNAi) 方法探讨了 ACC α 在乳腺癌细胞存活中的作用。我们发现，癌细胞中 ACC α 或脂肪酸合酶 (FAS) 基因的特异性沉默会导致棕榈酸合成大幅减少。细胞内棕榈酸库的消耗与细胞凋亡的诱导以及活性氧（ROS）的形成和线粒体损伤有关。 ACC α mRNA 的小干扰 RNA (siRNA) 抗性形式的表达阻止了 ACC α-RNAi 的作用，但未能阻止 FAS 基因沉默的作用。此外，在培养基中添加棕榈酸酯或抗氧化剂维生素E可完全拯救细胞免受ACC α和FAS siRNA诱导的细胞凋亡。最后，人类乳腺上皮细胞对针对 ACC α 或 FAS 的 RNAi 具有抵抗力。这些数据证实了脂肪生成在癌细胞存活中的重要性，并表明该途径代表了抗肿瘤治疗的关键目标，然而，可能需要特定的饮食建议才能发挥全部功效。
Activation of de novo fatty acid synthesis is a characteristic feature of cancer cells. We have recently described an interaction between acetyl-CoA carboxylase alpha (ACC alpha), a key enzyme in fatty acid synthesis, and BRCA1, which indicates a possible connection between lipid synthesis and genetic factors involved in susceptibility to breast and ovarian cancers. For this reason, we explored the role of ACC alpha in breast cancer cell survival using an RNA interference (RNAi) approach. We show that specific silencing of either the ACC alpha or the fatty acid synthase (FAS) genes in cancer cells results in a major decrease in palmitic acid synthesis. Depletion of the cellular pool of palmitic acid is associated with induction of apoptosis concomitant with the formation of reactive oxygen species (ROS) and mitochondrial impairment. Expression of a small interfering RNA (siRNA)-resistant form of ACC alpha mRNA prevented the effect of ACC alpha-RNAi but failed to prevent the effect of FAS gene silencing. Furthermore, supplementation of the culture medium with palmitate or with the antioxidant vitamin E resulted in the complete rescue of cells from both ACC alpha and FAS siRNA-induced apoptosis. Finally, human mammary epithelial cells are resistant to RNAi against either ACC alpha or FAS. These data confirm the importance of lipogenesis in cancer cell survival and indicate that this pathway represents a key target for antineoplastic therapy that, however, might require specific dietary recommendation for full efficacy.