Open AccessOverexpression of RhoA enhances peritoneal dissemination: RhoA suppression with Lovastatin may be useful for ovarian cancer
Author(s) -
Horiuchi Akiko,
Kikuchi Norihiko,
Osada Ryosuke,
Wang Cuiju,
Hayashi Akiko,
Nikaido Toshio,
Konishi Ikuo
Publication year - 2008
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2008.00977.x
Subject(s) - rhoa , lovastatin , ovarian cancer , cancer research , in vivo , pravastatin , ovarian carcinoma , rock1 , biology , downregulation and upregulation , rho kinase inhibitor , endocrinology , medicine , cancer , rho associated protein kinase , kinase , microbiology and biotechnology , signal transduction , biochemistry , cholesterol , gene
Small guanosine triphosphatase RhoA has been known to re‐organize cytoskeletons and regulate cell migration. The present authors have previously reported that expression of RhoA is significantly increased in advanced ovarian carcinomas and also in the peritoneal disseminated lesions. The present study investigated whether overexpression of RhoA could alter the progressive behavior of ovarian cancer cells. The effect of various Rho inhibitors on the biological behavior of ovarian cancer cells in vitro and in vivo was also examined. A stable RhoA‐transfectant of an ovarian cancer cell line SKOV3 was generated and examined in vitro for alterations of proliferative activity and invasiveness, and also in the nude mice model for peritoneal dissemination. In addition, the effect of a specific Rho inhibitor (C3 exoenzyme), Rho kinase inhibitor (Y27632) and hydroxymethylglutaryl coenzyme A (HMG–CoA) reductase inhibitor (Lovastatin and Pravastatin) were studied in vitro and in vivo . Forced overexpression of RhoA did not alter proliferative activity but significantly increased the invasiveness in vitro , which was suppressed by addition of C3 exoenzyme, Y27834, Lovastatin and Pravastatin. In the nude mice model, the frequency of dissemination and the number of disseminated lesions were significantly increased in the RhoA transfectant than in the control. In addition, oral administration of Lovastatin significantly decreased the number of metastatic sites compared with the control. These findings suggest that upregulation and/or activation of RhoA play an important role in the peritoneal dissemination of ovarian carcinoma, and that Lovastatin might be a candidate for the possible, novel treatment for ovarian carcinoma patients with peritoneal dissemination. ( Cancer Sci 2008; 99: 2532–2539)