[Frontiers in Bioscience S2, 515-526, January 1, 2010]

Acetyl-CoA carboxylase-α as a novel target for cancer therapy

Chun Wang1, 2, 3, Sandeep Rajput3, Kounosuke Watabe3, Duan-Fang Liao1,2, Deliang Cao3

1School of Pharmaceutical Sciences, Central South University, Changsha, 410083, China,2Institute of Pharmacy and Pharmacology, College of Science and Technology, University of South China, Hengyang, 421001, China, 3Department of Medical Microbiology, Immunology, and Cell Biology, Simmons Cooper Cancer Institute, Southern Illinois University School of Medicine. 913 N. Rutledge Street, Springfield, IL 62794

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. ACC, fatty acid metabolism, and metabolic syndromes
4. Regulation of ACC expression and activity
4.1. ACC expression is regulated at both transcriptional and translational levels
4.2. ACC protein stability is mediated by protein-protein complexes
4.3. ACC activity is modulated by phosphorylation and allosteric mechanisms
5. Lipogenesis and ACCA expression in cancer cells
6. ACCA as a potential target for cancer therapeutics
7. Conclusion
8. Acknowledgement
9. References

1. ABSTRACT

Acetyl-CoA carboxylases (ACC) are rate-limiting enzymes in de novo fatty acid synthesis, catalyzing ATP-dependent carboxylation of acetyl-CoA to form malonyl-CoA. Malonyl-CoA is a critical bi-functional molecule, i.e., a substrate of fatty acid synthase (FAS) for acyl chain elongation (fatty acid synthesis) and an inhibitor of carnitine palmitoyltransferase I (CPT-I) for fatty acid beta-oxidation. Two ACC isoforms have been identified in mammals, i.e. ACC-alpha (ACCA, also termed ACC1) and ACC-beta (ACCB, also designated ACC2). ACC has long been used as a target for the management of metabolic diseases, such as obesity and metabolic syndrome, and various inhibitors have been developed in clinical trials. Recently, ACCA up-regulation has been recognized in multiple human cancers, promoting lipogenesis to meet the need of cancer cells for rapid growth and proliferation. Therefore, ACCA might be effective as a potent target for cancer intervention, and the inhibitors developed for the treatment of metabolic diseases would be potential therapeutic agents for cancer therapy. This review summarizes our recent findings and updates the current understanding of the ACCA with focus on cancer research.