Lysophosphatidic acid acyltransferase-beta: a novel target for induction of tumour cell apoptosis

Expert Opin Ther Targets. 2003 Oct;7(5):643-61. doi: 10.1517/14728222.7.5.643.

Abstract

Phosphatidic acid (PA) is a component of cellular membranes that is also a mediator of certain cell signalling functions associated with oncogenesis. These include ras/raf/Erk and Akt/mTor [1-3]. The authors have investigated whether it would be possible to interrupt these known oncogenic pathways through the inhibition of lysophosphatidic acid acyltransferase (LPAAT), an enzyme that catalyses the biosynthesis of PA. The expression and activity of the LPAAT-beta isoform are elevated in human tumours, and the respective gene displays transforming capacity when overexpressed in vitro. Inhibition by either genetic means or by isoform-specific small molecules results in a block to cell signalling pathways and apoptosis. Furthermore, the small-molecule inhibitors of LPAAT-beta are not cytotoxic to a number of normal cell types, including primary bone marrow progenitors, indicating a differential dependence of tumour cells on LPAAT-beta function. These discoveries indicate that LPAAT-beta represents a potential novel cancer therapy target.

Publication types

  • Review

MeSH terms

  • Acylation / drug effects
  • Acyltransferases / antagonists & inhibitors*
  • Acyltransferases / genetics
  • Acyltransferases / physiology
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects*
  • Carcinoma, Lewis Lung / drug therapy
  • Cell Division / drug effects
  • Cell Division / physiology
  • Cell Line, Tumor / drug effects
  • Cell Transformation, Neoplastic
  • Chromosomes, Human, Pair 9 / genetics
  • Drug Design*
  • Drug Evaluation, Preclinical
  • Genes, ras
  • Humans
  • Hydrocarbons, Halogenated / pharmacology
  • Hydrocarbons, Halogenated / therapeutic use
  • Lung Neoplasms / drug therapy
  • Mice
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / physiology
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Phosphatidic Acids / physiology
  • Protein Conformation
  • Protein Processing, Post-Translational / drug effects
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Triazines / pharmacology
  • Triazines / therapeutic use

Substances

  • Antineoplastic Agents
  • CT-32228
  • Hydrocarbons, Halogenated
  • Neoplasm Proteins
  • Phosphatidic Acids
  • Triazines
  • Acyltransferases
  • 2-acylglycerophosphate acyltransferase