Geranylgeranylacetone inhibits lysophosphatidic acid-induced invasion of human ovarian carcinoma cells in vitro.
BACKGROUND
Lysophosphatidic acid (LPA) induced a dose-dependent increase of cancer cell invasion by promoting Rho/Rho-associated kinase signaling. Prenylation of Rho is essential for regulating cell growth, motility, and invasion. Geranylgeranylacetone (GGA), an isoprenoid compound, is used clinically as an antiulcer drug. Recent findings suggested that GGA might inhibit the small GTPase activation by suppressing prenylation. The authors hypothesized that the anticancer effects of GGA result from the inhibition of Rho activation.


METHODS
The authors examined the effect of GGA using an in vitro invasion assay in human ovarian carcinoma cells, and analyzed the mechanism of the GGA effect on Rho activation, stress fiber formation and focal adhesion assembly, which are essential processes for cell invasion.


RESULTS
The induction of ovarian carcinoma cell invasion by LPA was inhibited by the addition of GGA in a dose-dependent manner. Treatment of cancer cells with GGA resulted in inactivation of Rho, changes in cell morphology, loss of stress fiber formation and focal adhesion assembly, and the suppression of tyrosine phosphorylation of focal adhesion proteins. The effect of GGA on cancer cells was partially prevented by the addition of geranylgeraniol, which is an intermediate of geranylgeranyl pyrophosphate and compensates geranylgeranylation of Rho.


CONCLUSIONS
The inhibition of LPA-induced invasion by GGA was, at least in part, derived from suppressed Rho activation by preventing geranylgeranylation.
Hashimoto
Kae
K
Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan.
Morishige
Ken-ichirou
K
Sawada
Kenjiro
K
Tahara
Masahiro
M
Shimizu
Shoko
S
Sakata
Masahiro
M
Tasaka
Keiichi
K
Murata
Yuji
Y
D000199:Actins / Q000187:drug effects; D000209:Acute-Phase Proteins / Q000378:metabolism*; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008246:Lysophospholipids / Q000037:antagonists & inhibitors*; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D010051:Ovarian Neoplasms / Q000473:pathology*; D051419:Paxillin; D010750:Phosphoproteins / Q000187:drug effects; D010766:Phosphorylation; D014407:Tumor Cells, Cultured
D000199:Actins; D000209:Acute-Phase Proteins; D003598:Cytoskeletal Proteins; D004224:Diterpenes; D008246:Lysophospholipids; C496061:PXN protein, human; D051419:Paxillin; D010750:Phosphoproteins; C010781:acute-phase protein rho; C032881:lysophosphatidic acid; C031049:geranylgeranylacetone