ATP citrate lyase: A central metabolic enzyme in cancer

• Published in: Cancer letters 2020-02, Vol.471, p.125-134
• Main Authors: Icard, Philippe, Wu, Zherui, Fournel, Ludovic, Coquerel, Antoine, Lincet, Hubert, Alifano, Marco
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Acetyl-CoA; Acetylation; ACLY; AKT; AKT protein; ATP citrate lyase; Binding sites; Biosynthesis; Breast cancer; Cell cycle; Citrate; Dehydrogenases; Energy metabolism; Enzymes; Fatty acids; Glycolysis; Growth factors; Hypoxia; Inhibitors; Kinases; Life Sciences; Localization; Medical prognosis; Metabolism; NADP; Oxaloacetate; Oxidation; Phosphorylation; Proteins; Transcription
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2019.12.010

ACLY links energy metabolism provided by catabolic pathways to biosynthesis. ACLY, which has been found to be overexpressed in many cancers, converts citrate into acetyl-CoA and OAA. The first of these molecules supports protein acetylation, in particular that of histone, and de novo lipid synthesis, and the last one sustains the production of aspartate (required for nucleotide and polyamine synthesis) and the regeneration of NADPH,H+(consumed in redox reaction and biosynthesis). ACLY transcription is promoted by SREBP1, its activity is stabilized by acetylation and promoted by AKT phosphorylation (stimulated by growth factors and glucose abundance). ACLY plays a pivotal role in cancer metabolism through the potential deprivation of cytosolic citrate, a process promoting glycolysis through the enhancement of the activities of PFK 1 and 2 with concomitant activation of oncogenic drivers such as PI3K/AKT which activate ACLY and the Warburg effect in a feed-back loop. Pending the development of specific inhibitors and tailored methods for identifying which specific metabolism is involved in the development of each tumor, ACLY could be targeted by inhibitors such as hydroxycitrate and bempedoic acid. The administration of citrate at high level mimics a strong inhibition of ACLY and could be tested to strengthen the effects of current therapies. •Cisplatin-based induction chemotherapy increases PD-L1 expression by tumor cells.•ACLY links catabolic pathways (glycolysis and glutaminolysis) with biosynthesis.•Acetyl-coA sustains acetylation of histone and of enzymes implied in metabolism.•Oxaloacetate metabolism furnished molecules for nucleotide synthesis and redox system.•Low cytosolic citrate promotes glycolysis and activation of PI3K/AKT pathways.