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Inhibition of lysophosphatidic acid acyltransferase disrupts proliferative and survival signals in normal cells and induces apoptosis of tumor cells

  1. Author:
    Coon, M.
    Ball, A.
    Pound, J.
    Ap, S.
    Hollenback, D.
    White, T.
    Tulinsky, J.
    Bonham, L.
    Morrison, D. K.
    Finney, R.
    Singer, J. W.

  2. Author Address

    Cell Therapeut, Seattle, WA 98117 USA Cell Therapeut, Seattle, WA 98117 USA NCI, Regulat Cell Growth Lab, Frederick, MD 21701 USA PanGenex, Seattle, WA USA Coon M Cell Therapeut, Seattle, WA 98117 USA
    1. Year: 2003
  2. Journal: Molecular Cancer Therapeutics
    1. 2
    2. 10
    3. Pages: 1067-1078
  4. Type of Article: Article
  1. 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 P13K/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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