Migita Toshiro, Narita Tadahito, Nomura Kimie, Miyagi Erika, Inazuka Fumika, Matsuura Masaaki, Ushijima Masaru, Mashima Tetsuo, Seimiya Hiroyuki, Satoh Yukitoshi, Okumura Sakae, Nakagawa Ken, Ishikawa Yuichi
Divisions of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
Cancer Res. 2008 Oct 15;68(20):8547-54. doi: 10.1158/0008-5472.CAN-08-1235.
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.
葡萄糖和脂质代谢增强是恶性细胞最常见的特性之一。ATP柠檬酸裂解酶（ACLY）是从头合成脂肪酸的关键酶，负责生成胞质乙酰辅酶A和草酰乙酸。为了评估其在肺癌进展中的作用，我们在此分析了一部分人肺腺癌细胞系中ACLY的表达，并显示其与磷脂酰肌醇-3激酶-Akt通路有关。将组成型活性Akt导入细胞可增强ACLY的磷酸化，而显性负性Akt则导致其磷酸化减弱。在人肺腺癌样本中，发现ACLY活性明显高于正常肺组织。免疫组织化学分析进一步显示，162例肿瘤中磷酸化ACLY过表达，与分期、分化程度及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敲低的细胞中发现细胞内脂质增加，而从头脂肪生成受到抑制。补充胰岛素可挽救ACLY抑制引起的增殖停滞；然而，相反地，脂肪酸棕榈酸酯诱导细胞死亡。综上所述，这些发现表明ACLY参与了与代谢异常相关的肺癌发病机制，可能提供一个新的治疗靶点。
