1. The Rho-kinase inhibitor HA-1077 suppresses proliferation/migration and induces apoptosis of urothelial cancer cells
- Author
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Hiromichi Shirataki, Takao Kamai, Naohiko Anzai, Ken-Ichiro Yoshida, Keitaro Hayashi, Akinori Masuda, Hideyuki Abe, Yoshitatsu Fukabori, Masahiro Yashi, Tomoya Mizuno, Yoshiyuki Yamaguchi, Hironori Betsunoh, and Hideo Yuki
- Subjects
Urologic Neoplasms ,Cancer Research ,Pathology ,medicine.medical_specialty ,RHOA ,Apoptosis ,Metastasis ,chemistry.chemical_compound ,Cell Movement ,1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine ,Cell Line, Tumor ,Lysophosphatidic acid ,Genetics ,medicine ,Humans ,Protein Kinase Inhibitors ,Rho-associated protein kinase ,Tumor Stem Cell Assay ,Cell Proliferation ,rho-Associated Kinases ,biology ,Cell growth ,business.industry ,Fasudil ,Cancer ,medicine.disease ,Immunohistochemistry ,Urinary Bladder Neoplasms ,Oncology ,chemistry ,Rho kinase inhibitor ,Cancer research ,biology.protein ,business ,Research Article - Abstract
Background Activation of Rho, one of the small GTPases, and its major downstream target Rho-kinase (ROCK) promotes the development and metastasis of cancer. We previously showed that elevation of Rho and ROCK expression was associated with tumor invasion, metastasis, and an unfavorable prognosis in patients with urothelial cancer of the bladder or upper urinary tract. Methods We investigated the effects of a ROCK inhibitor on the growth, migration, and apoptosis of bladder cancer cells. We also examined phosphorylation of RhoA (RhoA activity) by measuring its GTP-bound active form and assessed the expression of ROCK to explore the underlying molecular mechanisms. Results Lysophosphatidic acid (LPA) and geranylgeraniol (GGOH) induced an increase of cell proliferation and migration in association with promotion of RhoA activity and upregulation of ROCK expression. The ROCK inhibitor fasudil (HA-1077) suppressed cell proliferation and migration, and also induced apoptosis in a dose-dependent manner. HA-1077 dramatically suppressed the expression of ROCK-I and ROCK-II, but did not affect RhoA activity. Conclusions These findings suggest that ROCK could be a potential molecular target for the treatment of urothelial cancer.
- Published
- 2014
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