Current Molecular Pharmacology, 2011, 4, ???-??? 1 1874-4672/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd. Glycerophospholipid Synthesis as a Novel Drug Target Against Cancer Vincenza Dolce*, Anna Rita Cappello, Rosamaria Lappano and Marcello Maggiolini* Department of Pharmaco-Biology, University of Calabria, 87036 Rende (CS), Italy Abstract: Tumor cells display progressive changes in metabolism that correlate with malignancy, including development of a lipogenic phenotype. Highly proliferating cancer cells need to synthesise fatty acids de novo to continually provide glycerophospholipids particularly for membrane production. The synthesised fatty acids are also used for energy produc- tion through -oxidation and lipid modification of proteins. In addition, deregulated lipogenesis plays an important role in tumor cell survival and affects fundamental cellular processes, including signal transduction and gene expression. These observations suggest that enzymes involved in the pathways of lipid synthesis would be rational therapeutic targets in cancer. Over the past few decades, many substantial discoveries regarding enzymes and proteins acting in lipid synthesis have led to the current understanding of the complex signalling network implicated in the metabolic transduction path- ways. This review presents an overview of mammalian glycerophospholipid synthesis, signal transduction and cellular distribu- tion of the biochemical activities that produce distinct membrane lipid molecular species. Keywords: Cancer, Glycerophospholipid synthesis, Lipogenesis, PI3K/Akt pathway, Ras/Raf/ERK pathway. INTRODUCTION An altered metabolism is one of the most important fea- tures of cancer cells [1]. Initially, Otto Warburg observed enhanced anaerobic glycolysis in tumor cells [2, 3], thereaf- ter alterations in lipid metabolism have been also described [4]. The elevated glucose catabolism observed in cancer cells produces an excess of pyruvate. Pyruvate can be converted into either cytosolic lactate, which is secreted, or into mito- chondrial acetyl Coenzyme A (acetyl-CoA), which is con- verted into citrate within the mitochondria. There are two ways by which cancer cells can use citrate (Fig. 1): citrate can be processed by the Krebs' (or tricarboxylic acid, TCA) cycle or exported to the cytoplasm via citrate carrier (CIC), where it is cleaved by ATP citrate lyase (ACL), generating cytosolic acetyl-CoA, that may be considered a building block for fatty acid (FA) biosynthesis. Cancer cells prefer the second pathway, possibly due to the reduction in the mito- chondrial TCA cycle associated with malignant transforma- tion [5]. Highly proliferating cancer cells need to synthesize de novo fatty acids to continually provide glycerophospholipids for membrane production, thereby endogenously synthesized fatty acids are esterified predominantly to phospholipids rather than triacylglycerols, from the phosphatidic acid, in contrast to normal tissues [6] (Fig. 1). De novo fatty acid synthesis involves two key enzymes, acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). ACC carboxylates acetyl-CoA to form malonyl-CoA, which is converted by FAS to long-chain fatty acids. There- after, the fatty acid product is activated by Acyl-CoA *Address correspondence to this author at the Dept. of Pharmaco-Biology, University of Calabria, 87036 Rende (CS), Italy; Tel: +39 0984493177; Fax: +39 0984493270; E-mail: vdolce@unical.it. Tel: +39 0984493076; Fax: +39 0984493458; E-mail: marcellomaggiolini@yahoo.it synthetases (ACS) forming fatty acyl-CoA [7], which is a necessary substrate for phospholipid biosynthesis along with glycerol-3-phosphate. The first step of this metabolic path- way is the catalyzed formation of lysophosphatidic acid (LPA) from both glycerol-3-phosphate and fatty acyl-CoA by glycerol-3-phosphate acyltransferase (GPAT), which is thought to be a rate limiting step for all subsequent glycero- phospholipid biosynthesis. The next biosynthetic step is the formation of phosphatidic acid (PA) from LPA, which in turn is required for the biosynthesis of triacylglycerols and glycerophospholipids. This step is catalyzed by several lys- ophosphatidic acid acyltransferase enzymes (LPAATs) [8] (Fig. 1). Phospholipid biosynthesis is present in distinct cellular compartments such as mitochondria, peroxisomes and endo- plasmic reticulum. In this regard, in a recent study the SLC37A1 protein was localized in the endoplasmic reticu- lum, suggesting its potential involvement in the transport of glycerol-3-phosphate into the endoplamic reticulum and phospholipid biosynthesis [9]. This review focuses on recent advances in this field pro- viding a theoretical basis to consider the enzymes involved in the lipogenic pathways as new pharmacological targets in cancer cells. ENZYMES INVOLVED IN FATTY ACID SYNTHESIS ATP Citrate Lyase (ACL) A key enzyme linking glucose metabolism to lipid syn- thesis is ACL, a tetramer of 440kDa [10], which catalyzes the formation of acetyl-CoA and oxaloacetate in the cytosol from citrate and Coenzyme A (CoA) with the hydrolysis of ATP to ADP and phosphate (Fig. 1). Cytosolic acetyl-CoA is functionally important in several biosynthetic pathways, and is essential for lipogenesis. A marked increase of ACL ex- pression and activity has been reported in cancer cells [11- 13]. In addition, ACL overexpression or activation have been shown in bladder, breast, liver, stomach, colon, prostate and