title: Statins improve survival by inhibiting spontaneous metastasis and tumor growth in a mouse melanoma model.
abstract: Metastatic melanoma is a life-threatening disease for which no effective treatment is currently available. In melanoma cells, Rho overexpression promotes invasion and metastasis. However, the effect of statins on spontaneous metastasis and tumor growth remains unclear. In the present study, we investigated the mechanism of statin-mediated tumor growth and metastasis inhibition in an in vivo model. We found that statins significantly inhibited spontaneous metastasis and tumor growth. Statins inhibited the mRNA expression and enzymatic activities of matrix metalloproteinases (MMPs) in vivo and also suppressed the mRNA and protein expression of very late antigens (VLAs). Moreover, statins inhibited the prenylation of Rho as well as the phosphorylation of LIM kinase, serum response factor (SRF), and c-Fos downstream of the Rho signaling pathway. In addition, statins enhanced p53, p21, and p27 expression and reduced phosphorylation of cyclin-dependent kinase and expression of cyclin D1 and E2. These results indicate that statins suppress Rho signaling pathways, thereby inhibiting tumor metastasis and growth. Furthermore, statins markedly improved the survival rate in a metastasis model, suggesting that statins have potential clinical applications for the treatment of metastatic cancers.
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy Kowakae, Higashi-Osaka, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Tsubaki
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy Kowakae, Higashi-Osaka, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Takeda
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy Kowakae, Higashi-Osaka, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Kino
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy Kowakae, Higashi-Osaka, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Obata
authors.affiliation: Department of Food Science and Nutrition, Kinki University School of Agriculture Nara, Japan.
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Itoh
authors.affiliation: Department of Surgery, Kinki University School of Medicine Osakasayama, Osaka, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Imano
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy Kowakae, Higashi-Osaka, Japan ; Department of Pharmacy, Japanese Red Cross Society Wakayama Medical Center Wakayama, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Mashimo
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy Kowakae, Higashi-Osaka, Japan ; Department of Pharmacy, Japanese Red Cross Society Wakayama Medical Center Wakayama, Japan.
authors.forename: Daichiro
authors.initials: D
authors.lastname: Fujiwara
authors.affiliation: Department of Pharmacy, Japanese Red Cross Society Wakayama Medical Center Wakayama, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Sakaguchi
authors.affiliation: Department of Pathology, Kinki University School of Medicine Osakasayama, Osaka, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Satou
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy Kowakae, Higashi-Osaka, Japan.
authors.forename: Shozo
authors.initials: S
authors.lastname: Nishida
keywords: Rho; Statins; melanoma; metastasis; tumor growth