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ACLY (ATP-citrate lyase) is a cytosolic enzyme. It can catalyze the production of acetyl-CoA and oxaloacetate from citric acid and CoA while hydrolyzing ATP into ADP and phosphate. Acetyl-CoA is also required for protein modification during acetylation, such as histone acetylation. The ACLY gene is located on 17q21.2 of the human chromosome and contains 30 exons. The ACLY protein is a homotetramer of four identical subunits, each polypeptide chain contains 1101 amino acid residues. ACLY exhibits a high expression level in many different types of tumors, and inhibition of its expression inhibits the proliferation of certain types of tumor cells.
ACLY is most abundantly expressed in liver and white adipose tissue, but it is low in brain, heart, small intestine, and muscle. ACLY is also expressed in pancreatic beta cells and is actively expressed. ACLY is primarily a cytosolic enzyme, bounding to the endoplasmic reticulum in mammalian cells. However, recent research has found that in addition to the cytoplasm, ACLY is also present in small amounts in the nucleus of some animals, such as mouse embryonic fibroblasts, mouse pro-B lymphocytes, human glioblastoma cells, and human colon cancer cells.
ACLY Signaling Pathway
ACLY is a bridge between sugar metabolism, fatty acid synthesis and the mevalonate pathway. In the cytoplasm, ACLY catalyzes the conversion of citrate to acetyl-CoA, which is an important substrate for fatty acid synthesis and the mevalonate pathway. In the fatty acid synthesis pathway, acetyl-CoA is catalyzed by acetyl-CoA carboxylase (ACACA) to carboxylate and coverts to malonyl-CoA. Then fatty acid synthase (FASN) catalyzes the condensation of acetyl-CoA and malonyl-CoA to produce long-chain fatty acid palm acid. Acetyl-CoA is also a precursor of the mevalonate pathway. This pathway synthesizes farnesyl pyrophosphate (FPP), which is involved in cholesterol biosynthesis and can also be synthesized to geranylgeranyl pyrophosphate (GG-PP). FPP and GG-PP are involved in various protein farnesylation and geranyl geranlylation, also known as prenylation. In addition, acetyl-CoA is required for acetylation, such as histone acetylation, and the modified protein plays a key role in regulating global chromatin architecture and gene transcription. In addition, acetylation of modified proteins, which plays a key role in the regulation of global chromatin architecture and gene transcription, also requires acetyl-CoA.
Figure 1. Involvement of ATP citrate lyase in several metabolic pathways. (Liviu, et al. 2008).
ACLY Activity and Expression in Cancer Cells
The continuous division and proliferation of tumor cells require the consumption of large amounts of energy and macromolecules. One of the most critical features of this cell proliferation is the apparent abnormality of metabolic pathways. Of all the changes in metabolic characteristics, the synthesis of new fatty acids is particularly important. Most normal cells use predominantly exogenous lipids even in hyperproliferative states. Except for a few cells such as adipocytes and hepatocytes, normal fatty acid synthesis pathways in normal cells are inhibited. However, for tumor cells, there is no apprehension inhibition. The tumor cells synthesize a large number of lipids, which in turn triggers a series of reactions such as abnormal signal transduction, altered gene expression, and altered drug sensitivity. This process cannot be separated from ACLY's key role. ACLY has significantly improved enzymatic activity in a variety of tumor cells and is associated with the malignant progression of several tumors.
Studies have shown that ACLY is upregulated in the expression and activity of ACLY in lung, prostate, bladder, breast, ovarian, liver, gastric, and colon cancers. The expression of phosphorylated ACLY in human non-small cell lung cancer and epithelial ovarian cancer has been shown to be associated with tumor stage, differentiation, and poor prognosis. Therefore, at least for these two types of cancer, ACLY overexpression and activation are considered to be a statistically significant negative prognostic indicator. Lucenay et al. found that the abnormal localization of LMW-E isoforms in breast cancer cytoplasm can alter target binding and activation, contributing to LMW-E-induced tumorigenicity. This tumorigenicity is formed by the up-regulating of ACLY enzyme activity to Increase the formation of lipid droplets through LMW-E. For colon cancer, Xie et al. assessed the effect of functional single nucleotide polymorphisms (SNPs) in the ACLY gene on the recurrence and survival of patients with colorectal cancer (CRC), confirming that the SNPs in the ACLY gene can be used independently as a prognostic indicator of advanced CRC patients.
In tumor cells, phosphorylated ACLY can be directly regulated by AKT. ACLY expression is mainly regulated by the transcription factor SREBP-1 (sterol regulatory element binding protein-1). SREBP-1 AKT upregulates ACLY at the mRNA level through AKT signaling. However, studies have shown that the expression level of ACLY protein is independent of SREBP-1. It is known that activation of the PI3K/AKT pathway activates ACLY activity primarily through phosphorylation of ACLY rather than transcriptional upregulation. Phosphorylation of ACLY contributes to the stability of its proteins. The ACLY phosphorylation sites Thr446, Ser450 and Ser454 were shown to be phosphorylated in vitro and PI3K inhibitor treatment in lung cancer cells was confirmed to have no significant effect on dephosphorylation and ACLY inactivation. Therefore, ACLY activity was also It is controlled by other ways. Studies have shown that ACLY is phosphorylated at different sites by other kinases, such as nucleoside diphosphate kinases and cyclic AMP-dependent protein kinases. In addition, glucagon, insulin, vasopressin, and transforming growth factor beta 1 promote phosphorylation of ACLY.
ACLY Inhibition and Tumor Therapy
The increase in the activity and expression of ACLY in cancer cells indicates that ACLY inhibition may be an effective method to treat cancer. No matter in vitro or in vivo, ACLY inhibitors such as RNA interference or drug inhibitors can cause tumor cell growth arrest.
Some ACLY inhibitors have been shown to block fatty acid synthesis and/or cholesterol biosynthesis. Migita et al. studied the effect of ACLY inhibition on lipid metabolism and found that ACLY consumption blocked C16-C18 fatty acid chain elongation in triglycerides (TG) but did not block other lipids. Wang et al. showed that the expression of ACLY significantly increased in breast cancer compared with normal tissues. Silencing of endogenous ACLY expression by siRNA in MCF-7 cells can inhibit cell viability and increase apoptosis, suggesting that ACLY-related inhibitors may be a potential treatment for breast cancer. Irinotecan is usually used for first-line and second-line treatment of patients with metastatic colorectal cancer. The active metabolite is SN38. Zhou et al. found that overexpressing exogenous ACLY in colorectal cancer cells lead to significant chemoresistance to SN38. The combined suppression of AKT signaling and ACLY successfully converted SN38-resistant cells back to SN38, thereby increasing the therapeutic effect of irinotecan.
In addition, the knock-out of ACLY in tumor cells can significantly reduce the occurrence of AKT-involved tumors in vivo. Hanai et al. found that ACLY knockout causes tumor suppression and induces differentiation. ACLY knockout can reverse epithelial-mesenchymal transition (EMT) in lung cancer cells. EMT is usually associated with the process of inducing stem cells, demonstrating that ACLY knockout can affect cancer stem cells. It was also determined that most of the effects of ACLY knockout are signaling through the PI3K pathway, but not the Ras-mitogen-activated protein kinase (RMAPK) pathway.
Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a member of the transmembrane metalloproteinase family and plays an important role in the degradation of cell matrices, thereby regulating cell migration and invasion. In Bcr-ABl-positive leukemia cells, the distribution of MT1-MMP is consistent with the distribution of F-actin-rich structures, and the ABI1 pathway is essential in maintaining the polar distribution of MT1-MMP. The knock-down of ABI1 in p185wt-Bcr-Abl-positive leukemia cells with small hairpin RNA (shRNA) technology can significantly inhibit Bcr-ABl-induced intracellular MT1-MMP polarity distribution, thereby inhibiting cell invasion and migration.