ATP citrate lyase: activation and therapeutic implications in non-small cell lung cancer.

Abstract

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.

• Authors: Toshiro Migita, Tadahito Narita, Kimie Nomura, Erika Miyagi, Fumika Inazuka, Masaaki Matsuura, Masaru Ushijima, Tetsuo Mashima, Hiroyuki Seimiya, Yukitoshi Satoh, Sakae Okumura, Ken Nakagawa, Yuichi Ishikawa
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 20 Pg. 8547-54 (Oct 15 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 18922930 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Citrate (pro-S)-Lyase
• Proto-Oncogene Proteins c-akt

Topics

• ATP Citrate (pro-S)-Lyase (antagonists & inhibitors, genetics, physiology)
• Adenocarcinoma (drug therapy, enzymology, etiology)
• Animals
• Carcinoma, Non-Small-Cell Lung (drug therapy, enzymology, mortality, pathology)
• Cell Line, Tumor
• Enzyme Activation
• Humans
• Lung Neoplasms (drug therapy, enzymology, mortality, pathology)
• Mice
• Phosphorylation
• Prognosis
• Proto-Oncogene Proteins c-akt (genetics)