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Cell Signal. 2004 Oct;16(10):1141-51.

Protein kinase A inhibits lysophosphatidic acid induction of serum response factor via alterations in the actin cytoskeleton.

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School of Biology and Petit Institute for Biosciences and Bioengineering, Georgia Institute of Technology, 315 Ferst Drive, Atlanta, GA 30332-0363, USA.


Lysophosphatidic acid (LPA; 1-acyl-2-hydroxy-sn-glycero-3-phosphate) is a lipid growth factor that stimulates the proliferation of ovarian cancer cells. Recent studies indicate that elevation of cellular cAMP levels inhibits ovarian epithelial cancer cell growth. In this study, we investigated the effects of elevating cellular cAMP levels on LPA stimulation of OVCAR-3 ovarian cancer cell growth and on LPA stimulation of the serum response factor (SRF) transcription factor. Treatment of OVCAR-3 cells with forskolin and isobutylmethylxanthine (IBMX; 3-Isobutyl-1-methylxanthine) inhibited LPA stimulation of growth. LPA stimulation of SRF-mediated transcription was also inhibited in OVCAR-3 cells that were incubated with forskolin, dibutyryl cyclic AMP (db-cAMP), or paired cAMP analogues (N(6)-mono-tert-butylcarbamoyladenosine-3', 5'-cyclic monophosphate [6-MBC-cAMP] and Sp-5,6-DCl-BIMPS), which selectively activate type II protein kinase A. In contrast, incubation with a cAMP analogue (8-(4-chloro-phenylthio)-2'-O-methyadenosine-3',5'-cyclic monophosphate [8CPT-2Me-cAMP]) that specifically activates the cAMP inducible Rap1 exchange factor, Epac, did not inhibit SRF. Similar results were obtained when HepG2 hepatoma cells, which do not express endogenous LPA receptors, were transfected with a single LPA receptor (LPA(1)). We observed that treatment of OVCAR-3 cells with forskolin greatly reduced both F-actin staining and focal adhesion labeling with anti-paxillin antibodies. Treatment of OVCAR-3 cells with the F-actin stabilizing compound, jasplakinolide, prevented the protein kinase A (PKA)-mediated inhibition of SRF. These results suggest that PKA inhibits LPA stimulation of SRF by promoting the dissolution of F-actin and that this is likely to contribute to the cAMP-mediated inhibition of ovarian cancer cell growth.

[Indexed for MEDLINE]

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