geranylgeranylacetone and lysophosphatidic-acid

Topics: Animals; Antineoplastic Agents; Cell Hypoxia; Cyclooxygenase 2; Diterpenes; Female; Humans; Interleukins; Intracellular Signaling Peptides and Proteins; Lysophospholipids; Membrane Lipids; Mice; Multienzyme Complexes; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Neovascularization, Pathologic; Ovarian Neoplasms; Peptide Hydrolases; Phosphodiesterase I; Phospholipases A; Phosphoric Diester Hydrolases; Pyrophosphatases; Receptors, Lysophosphatidic Acid; Signal Transduction; Sphingosine; Vascular Endothelial Growth Factor A

Geranylgeranylacetone (GGA), an isoprenoid compound, is an anti-ulcer drug developed in Japan. In our previous study, GGA was shown to inhibit ovarian cancer invasion by attenuating Rho activation [K. Hashimoto, K. Morishige, K. Sawada, M. Tahara, S. Shimizu, M. Sakata, K. Tasaka, Y. Murata, Geranylgeranylacetone inhibits lysophosphatidic acid-induced invasion of human ovarian carcinoma cells in vitro. Cancer 103 (2005) 1529-1536.]. In the present study, GGA treatment inhibited ovarian cancer progression in vitro and suppressed the tumor growth and ascites in the in vivo ovarian cancer model. In vitro analysis, treatment of cancer cells by GGA resulted in the inhibition of cancer cell proliferation, the inactivation of Ras, and the suppression of tyrosine phosphorylation of mitogen-activated protein kinase (MAPK). In conclusion, this is the first report that GGA inhibited ovarian cancer progression and the anti-tumor effect by GGA is, at least in part, derived not only from the suppression of Rho activation but also Ras-MAPK activation.

Topics: Animals; Antineoplastic Agents; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Disease Progression; Diterpenes; Dose-Response Relationship, Drug; Female; Humans; Lysophospholipids; Mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinases; Ovarian Neoplasms; Phosphorylation; ras Proteins; Time Factors; Xenograft Model Antitumor Assays

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.. 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.. 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.. The inhibition of LPA-induced invasion by GGA was, at least in part, derived from suppressed Rho activation by preventing geranylgeranylation.

Topics: Actins; Acute-Phase Proteins; Cell Shape; Cell Survival; Cytoskeletal Proteins; Diterpenes; Dose-Response Relationship, Drug; Female; Gene Expression Regulation; Humans; Lysophospholipids; Neoplasm Invasiveness; Ovarian Neoplasms; Paxillin; Phosphoproteins; Phosphorylation; Tumor Cells, Cultured