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. [Cancer Res 2008;68(20):8547–54]
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ACLY activity is elevated in cancers.
“ACLY activity is elevated in cancers (Migita et al., 2008), and targeting ACLY genetically or chemically prevents xenograft tumor formation and proliferation (Adam et al., 2013; Bauer et al., 2005; Hatzivassiliou et al., 2005; Migita et al., 2008).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Migita et al., 2008
ACLY, ACC, and FASN are frequently upregulated in transformed cells, and their inhibition reduces tumor cell growth in vitro and in vivo.
“In fact, all three major components involved in fatty acyl chain biosynthesis – ACLY, ACC and FASN – are frequently upregulated in transformed cells; furthermore, their inhibition reduces tumor cell growth in vitro and in vivo (Chajes et al., 2006; Flavin et al., 2010; Migita et al., 2008; Milgraum et al., 1997).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Migita et al., 2008
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- Authors
- Migita, T., Narita, T., Nomura, K., Miyagi, E., Inazuka, F., Matsuura, M., Ushijima, M., Mashima, T., Seimiya, H., Satoh, Y., Okumura, S., Nakagawa, K., & Ishikawa, Y.
- Affiliations
- 1Pathology and Divisions of
- Zenyaku Kogyo (Japan) (JP)
- 2Cancer Genomics, The Cancer Institute,
- 3Bioinformatics Group, Genome Center,
- 4Division of Molecular Biotherapy, Cancer Chemotherapy Center,
- The Cancer Institute Hospital (JP)
- ORCID
- Venue
- Cancer Research
- Published
- 2008-10-15
- Volume
- 68
- Issue
- 20
- Pages
- 8547-8554
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2136765222
- Cited by
- 403
- References
- 45
- Citations by year
- 2026: 17 · 2025: 16 · 2024: 32 · 2023: 26 · 2022: 36 · 2021: 48 · 2020: 34 · 2019: 24 · 2018: 25 · 2017: 21 · 2016: 17 · 2015: 21 · 2014: 20 · 2013: 22 · 2012: 17
- FWCI
- 2.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- ATP citrate lyase, non-small cell lung cancer, lung adenocarcinoma, de novo lipogenesis, lipogenesis, Akt signaling, PI3K/Akt signaling, acetyl-CoA, cancer metabolism, RNA interference, insulin, palmitate, cell proliferation, prognostic factors, therapeutic target
- MeSH terms
- Adenocarcinoma, Animals, ATP Citrate (pro-S)-Lyase, Carcinoma, Non-Small-Cell Lung, Enzyme Activation, Humans, Lung Neoplasms, Phosphorylation, Prognosis, Cell Line, Tumor, Proto-Oncogene Proteins c-akt, Mice
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