ATP Citrate Lyase: Activation and Therapeutic Implications in Non-Small Cell Lung Cancer
ATP Citrate Lyase: Activation and Therapeutic Implications in Non-Small Cell Lung Cancer
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DOI：
10.1158/0008-5472.can-08-1235
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发表时间：
2008-10-15
期刊：
影响因子：
11.2
通讯作者：
Ishikawa, Yuichi
中科院分区：
文献类型：
--
作者：
Migita, Toshiro;Narita, Tadahito;Ishikawa, Yuichi
增强的糖脂代谢是恶性细胞最常见的特性之一。ATP柠檬酸裂解酶（ACLY）是从头脂肪酸合成的关键酶，负责产生胞质乙酰辅酶A和草酰乙酸。为了评估其在肺癌进展中的作用，我们在此分析了人肺腺癌细胞系亚群中ACLY的表达，并显示其与磷脂酰肌醇 - 3激酶 - Akt通路相关。将组成型活性Akt引入细胞增强了ACLY的磷酸化，而显性失活Akt则导致其减弱。在人肺腺癌样本中，发现ACLY活性显著高于正常肺组织。免疫组织化学分析进一步表明，162个肿瘤中磷酸化ACLY过表达，与分期、分化程度和较差的预后密切相关。最后，为了展示ACLY抑制在肺癌治疗中的治疗潜力和机制，我们评估了靶向ACLY的RNA干扰对A549细胞脂肪生成和细胞增殖的影响。ACLY抑制导致体外和体内生长停滞。有趣的是，在ACLY敲低细胞中发现细胞内脂质增加，而从头脂肪生成受到抑制。补充胰岛素可以挽救由ACLY抑制引起的增殖停滞；然而，相反，脂肪酸棕榈酸酯诱导细胞死亡。综上所述，这些发现表明ACLY参与与代谢异常相关的肺癌发病机制，并可能提供一个新的治疗靶点。[《癌症研究》2008年；68(20):8547 - 54]
Enhanced glucose and lipid metabolism is one of the most common properties of malignant cells. ATP citrate lyase (ACLY) is a key enzyme of de novo fatty acid synthesis responsible for generating cytosolic acetyl-CoA and oxaloacetate. To evaluate its role in lung cancer progression, we here analyzed ACLY expression in a subset of human lung adenocarcinoma cell lines and showed a relationship with the phosphatidyl-inositol-3 kinase-Akt pathway. The introduction of constitutively active Akt into cells enhanced the phosphorylation of ACLY, whereas dominant-negative Akt caused attenuation. In human lung adenocarcinoma samples, ACLY activity was found to be significantly higher than in normal lung tissue. Immunohistochemical analysis further showed phosphorylated ACLY overexpression in 162 tumors, well-correlating with stage, differentiation grade, and a poorer prognosis. Finally, to show the therapeutic potential and mechanism of ACLY inhibition for lung cancer treatment, we assessed the effect of RNA interference targeting ACLY on lipogenesis and cell proliferation in A549 cells. ACLY inhibition resulted in growth arrest in vitro and in vivo. Interestingly, increased intracellular lipids were found in ACLY knockdown cells, whereas de novo lipogenesis was inhibited. Supplementation of insulin could rescue the proliferative arrest elicited by ACLY inhibition; however, in contrast, fatty acid palmitate induced cell death. Taken together, these findings suggest that ACLY is involved in lung cancer pathogenesis associated with metabolic abnormality and might offer a novel therapeutic target. [Cancer Res 2008;68(20):8547-54]