This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Migita, T. Articles by Ishikawa, Y. Search for Related Content PubMed PubMed Citation Articles by Migita, T. Articles by Ishikawa, Y.

ATP Citrate Lyase: Activation and Therapeutic Implications in Non–Small Cell Lung Cancer

Divisions of ¹ Pathology and ² Cancer Genomics, The Cancer Institute, ³ Bioinformatics Group, Genome Center, ⁴ Division of Molecular Biotherapy, Cancer Chemotherapy Center, ⁵ Department of Thoracic Surgical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, and ⁶ Zenyaku Kogyo Co., Ltd., Tokyo, Japan

Requests for reprints: Toshiro Migita, Division of Pathology, The Cancer Institute of Japanese Foundation for Cancer Research, 3-10-6, Ariake, Koto-ku, Tokyo, Japan, 135-8550. Phone: 3-3520-0111; Fax: 3-3570-0558; E-mail: toshiro.migita{at}jfcr.or.jp.

Key Words: ATP citrate lyase • Akt • non–small cell lung cancer

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]