Glycerophospholipid Synthesis as a Novel Drug Target Against Cancer

Vincenza      Dolce; Anna      Rita Cappello; Rosamaria      Lappano; Marcello      Maggiolini

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 production through β-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 pathways.

This review presents an overview of mammalian glycerophospholipid synthesis, signal transduction and cellular distribution of the biochemical activities that produce distinct membrane lipid molecular species.

Keywords: Cancer, Glycerophospholipid synthesis, Lipogenesis, PI3K/Akt pathway, Ras/Raf/ERK pathway, ATP Citrate Lyase, Acetyl-CoA Carboxylase, Fatty Acid Synthase, Glycerol-3-Phosphate Acyltransferase, Lysophosphatidic Acid Acyltransferase