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Vol. 62, Issue 3, 660-671, September 2002
Departments of Cancer Biology (L.M.B., K.L.C., J.L., Y.X.) and
Gynecology and Obstetrics (Y.X.), Cleveland Clinic Foundation,
Cleveland, Ohio; and Department of Chemistry, Cleveland State
University, Cleveland, Ohio (L.M.B., Y.X.)
The signaling pathways that lysophosphatidic acid (LPA) and
sphingosine-1-phosphate (S1P) use to activate Akt in ovarian cancer cells are investigated here. We show for the first time, with the use
of both pharmacological and genetic inhibitors, that the kinase
activity and S473 phosphorylation of Akt induced by LPA and S1P
requires both mitogen-activated protein (MAP) kinase kinase (MEK) and
p38 MAP kinase, and MEK is likely to be upstream of p38, in HEY ovarian
cancer cells. The requirement for both MEK and p38 is cell type- and
stimulus-specific. Among 12 cell lines that we tested, 11 respond to
LPA and S1P and all of the responsive cell lines require p38 but only
nine of them require MEK. Among different stimuli tested,
platelet-derived growth factor stimulates S473 phosphorylation of Akt
in a MEK- and p38-dependent manner. However, epidermal growth factor,
thrombin, and endothelin-1-stimulated Akt S473 phosphorylation require
p38 but not MEK. Insulin, on the other hand, stimulates Akt S473
phosphorylation independent of both MEK and p38 in HEY cells. T308
phosphorylation stimulated by LPA/S1P requires MEK but not p38
activation. MEK and p38 activation were sufficient for Akt S473 but not
T308 phosphorylation in HEY cells. In contrast to S1P and PDGF, LPA
requires Rho for Akt S473 phosphorylation, and Rho is upstream of
phosphatidylinositol 3-kinase (PI3-K). LPA/S1P-induced Akt activation
may be involved in cell survival, because LPA and S1P treatment in HEY
ovarian cancer cells results in a decrease in paclitaxel-induced
caspase-3 activity in a PI3-K/MEK/p38-dependent manner.
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