Inhibition of lysophosphatidic acid acyltransferase beta disrupts proliferative and survival signals in normal cells and induces apoptosis of tumor cells.
Mol Cancer Ther
; 2(10): 1067-78, 2003 Oct.
Article
em En
| MEDLINE
| ID: mdl-14578472
ABSTRACT
Lysophosphatidic acid acyltransferase beta (LPAAT-beta) is an intrinsic membrane protein that catalyzes the synthesis of phosphatidic acid (PA) from lysoPA. Given that PA is a cofactor in a number of signaling cascades that are constitutively active in tumors, we evaluated the role of PA produced by LPAAT-beta in Xenopus oocyte meiotic maturation assays and an isoform-specific inhibitor of LPAAT-beta in mammalian cell assays. We found that ectopic overexpression of LPAAT-beta cooperates in activation of the Ras/Raf/Erk pathway in Xenopus oocytes and that inhibition of LPAAT-beta inhibits signaling in both the Ras/Raf/Erk and PI3K/Akt pathways. When LPAAT-beta activity is suppressed by CT32228 (N-(4-bromo-phenyl)-6-(5-chloro-2-methyl-phenyl)-[1,3,5]triazine-2,4-diamine), an isoform-specific noncompetitive inhibitor, tumor cells undergo mitotic catastrophe while most normal cells simply arrest or become quiescent. The data presented here suggest that PA produced by LPAAT-beta plays an important role in signaling pathways critical to tumor cell survival.
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Base de dados:
MEDLINE
Assunto principal:
Aciltransferases
/
Apoptose
Idioma:
En
Ano de publicação:
2003
Tipo de documento:
Article