ATP Citrate Lyase (ACLY): A Promising Target for Cancer Prevention and Treatment

Abstract

ATP citrate lyase (ACLY), an important enzyme involved in lipid biogenesis linked with glucose metabolism, catalyzes the conversion of citrate to oxaloacetic acid (OAA) and acetyl-CoA. The obtained acetyl-CoA is required for lipid synthesis during membrane biogenesis, as well as for histone acetylation reactions to regulate the expression of certain proteins in aberrantly proliferating cancer cells. Studies have shown a role for ACLY in tumorigenesis whereby increased levels of the enzyme leads to increased metabolic activity via activation of Akt signaling. Increasing lines of evidence suggest that enzymes involved in lipid biogenesis play a significant role in cancer cell proliferation and progression. In many cancer types such as glioblastoma, colorectal cancer, breast cancer, non-small cell lung cancer, hepatocellular carcinoma etc., the level of ACLY has been found to be quite high as compared to normal cells. Cancer cell growth related to overexpression of ACLY can be inhibited by using chemical inhibitors or by the knockdown of ACLY gene. Inhibition of ACLY leads to changes in cancer cell metabolism that promotes tumor growth and proliferation. This review summarizes the role of ACLY in cancer development and its inhibitors in cancer treatment.

AGXT2L1 is down-regulated in heptocellular carcinoma and associated with abnormal lipogenesis

“…PE could be made by fatty acid esterification of lyso-PE by lyso-PE acyltransferase and then converted to PS and PC 17. Based on this, previous studies concluded that enhanced lipogenesis in cancer is simply a result of dysregulation and abnormal activation of crucial enzymes involved in fatty acid synthesis, such as ATP-citrate lyase (ACLY),7 18 19 acetyl-CoA carboxylase (ACC),20 fatty acid synthase (FASN)21 and peroxisome proliferative activated receptor gamma coactivator 1 α (PGC-1α) 22. For instance, ACLY, which is highly expressed in tumours, can catalyse citrate into acetyl-coenzyme to provide the raw materials for fatty acid synthesis,18 while PGC-1α can increase expression of the key enzymes for DNL (ie, ACC and FASN), thus promoting cancer progression 22…”

Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma

“…For instance, ACLY increased expression and activity have been reported in cancer cells, where small RNA interference (siRNA)-directed and pharmacological inhibition of ACLY strongly reduced the proliferation and survival of cancer cells. 25 Similarly, knockdown of ACAC, FASN, and SCD1 by siRNA or inhibition of ACC or FASN with small molecular inhibitors were found to impair tumor cell proliferation and induces apoptosis in various in vitro and in vivo cancer models. 22,26,27 Altogether, this body of information supports a pivotal role of lipogenic proteins and de novo lipid synthesis in cancer initiation and progression.…”

CD147 reprograms fatty acid metabolism in hepatocellular carcinoma cells through Akt/mTOR/SREBP1c and P38/PPARα pathways

“…Continuous de novo lipogenesis provides cancer cells with membrane building blocks, signaling lipid molecules and posttranslational modifications of proteins to support rapid cell proliferation [1,2]. Furthermore, the expression and activity of many key enzymes involved in de novo fatty acid synthesis, such as ATP citrate lyase (ACLY), acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN), are up-regulated and associated with poor clinical outcomes in many types of cancers [3][4][5]. However, mechanisms underlying the increased lipogenesis in cancers are not completely understood.…”