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

Affiliations

• PMID: 18922930
• DOI: 10.1158/0008-5472.CAN-08-1235

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

Toshiro Migita et al. Cancer Res. 2008.

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.

Similar articles

• ATP citrate lyase knockdown induces growth arrest and apoptosis through different cell- and environment-dependent mechanisms.

  Zaidi N, Royaux I, Swinnen JV, Smans K. Zaidi N, et al. Mol Cancer Ther. 2012 Sep;11(9):1925-35. doi: 10.1158/1535-7163.MCT-12-0095. Epub 2012 Jun 20. Mol Cancer Ther. 2012. PMID: 22718913

• Prognostic impact of the combination of glucose transporter 1 and ATP citrate lyase in node-negative patients with non-small lung cancer.

  Osugi J, Yamaura T, Muto S, Okabe N, Matsumura Y, Hoshino M, Higuchi M, Suzuki H, Gotoh M. Osugi J, et al. Lung Cancer. 2015 Jun;88(3):310-8. doi: 10.1016/j.lungcan.2015.03.004. Epub 2015 Mar 23. Lung Cancer. 2015. PMID: 25837797

• Glucose-dependent de novo lipogenesis in B lymphocytes: a requirement for atp-citrate lyase in lipopolysaccharide-induced differentiation.

  Dufort FJ, Gumina MR, Ta NL, Tao Y, Heyse SA, Scott DA, Richardson AD, Seyfried TN, Chiles TC. Dufort FJ, et al. J Biol Chem. 2014 Mar 7;289(10):7011-7024. doi: 10.1074/jbc.M114.551051. Epub 2014 Jan 27. J Biol Chem. 2014. PMID: 24469453 Free PMC article.

• ATP citrate lyase (ACLY): a promising target for cancer prevention and treatment.

  Khwairakpam AD, Shyamananda MS, Sailo BL, Rathnakaram SR, Padmavathi G, Kotoky J, Kunnumakkara AB. Khwairakpam AD, et al. Curr Drug Targets. 2015;16(2):156-63. doi: 10.2174/1389450115666141224125117. Curr Drug Targets. 2015. PMID: 25537655 Review.

• ATP citrate lyase (ACLY) inhibitors: An anti-cancer strategy at the crossroads of glucose and lipid metabolism.

  Granchi C. Granchi C. Eur J Med Chem. 2018 Sep 5;157:1276-1291. doi: 10.1016/j.ejmech.2018.09.001. Epub 2018 Sep 1. Eur J Med Chem. 2018. PMID: 30195238 Review.

Cited by

• Targeting Cancer Metabolism and Current Anti-Cancer Drugs.

  Sukjoi W, Ngamkham J, Attwood PV, Jitrapakdee S. Sukjoi W, et al. Adv Exp Med Biol. 2021;1286:15-48. doi: 10.1007/978-3-030-55035-6_2. Adv Exp Med Biol. 2021. PMID: 33725343 Review.

• A two-way street: reciprocal regulation of metabolism and signalling.

  Wellen KE, Thompson CB. Wellen KE, et al. Nat Rev Mol Cell Biol. 2012 Mar 7;13(4):270-6. doi: 10.1038/nrm3305. Nat Rev Mol Cell Biol. 2012. PMID: 22395772 Review.

• Exosome-mediated metabolic reprogramming: the emerging role in tumor microenvironment remodeling and its influence on cancer progression.

  Yang E, Wang X, Gong Z, Yu M, Wu H, Zhang D. Yang E, et al. Signal Transduct Target Ther. 2020 Oct 19;5(1):242. doi: 10.1038/s41392-020-00359-5. Signal Transduct Target Ther. 2020. PMID: 33077737 Free PMC article. Review.

• ARHGEF3 regulates the stability of ACLY to promote the proliferation of lung cancer.

  Zhou F, Ai W, Zhang Y, Hu Q, Gan M, Wang JB, Han T. Zhou F, et al. Cell Death Dis. 2022 Oct 14;13(10):870. doi: 10.1038/s41419-022-05297-4. Cell Death Dis. 2022. PMID: 36241648 Free PMC article.

• Mucins reprogram stemness, metabolism and promote chemoresistance during cancer progression.

  Marimuthu S, Rauth S, Ganguly K, Zhang C, Lakshmanan I, Batra SK, Ponnusamy MP. Marimuthu S, et al. Cancer Metastasis Rev. 2021 Jun;40(2):575-588. doi: 10.1007/s10555-021-09959-1. Epub 2021 Apr 4. Cancer Metastasis Rev. 2021. PMID: 33813658 Free PMC article. Review.

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Silverchair Information Systems

• Other Literature Sources

  • The Lens - Patent Citations Database

• Medical

  • MedlinePlus Health Information