ct-32228 and Carcinoma--Lewis-Lung

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.

Topics: Acylation; Acyltransferases; Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Lewis Lung; Cell Division; Cell Line, Tumor; Cell Transformation, Neoplastic; Chromosomes, Human, Pair 9; Drug Design; Drug Evaluation, Preclinical; Genes, ras; Humans; Hydrocarbons, Halogenated; Lung Neoplasms; Mice; Neoplasm Proteins; Neoplasms; Phosphatidic Acids; Protein Conformation; Protein Processing, Post-Translational; Signal Transduction; Triazines