title: Fasudil suppresses fibrosarcoma growth by stimulating secretion of the chemokine CXCL14/BRAK.
abstract: We previously reported that chemokine CXCL14/BRAK (BRAK) has antitumor activity in several carcinoma cells indicating that BRAK secretion suppresses carcinoma cells. Ras-homologous small GTPase (RhoA) and Rho-associated coiled-coil-containing protein kinase (ROCK) are important regulators of secretory processes, and activation of the RhoA/ROCK signaling pathway stimulates tumor invasion and metastasis. We investigated the effects of fasudil, a specific ROCK inhibitor, on BRAK secretion and tumor progression in mesenchymal fibrosarcoma cells (MC57). We demonstrated the antitumor activity of secreted BRAK using MC57 transplantation of BRAK in overexpressed transgenic mice. Further, to eliminate the influence of change in the mRNA expression of endogenous BRAK, we produced stable MC57 cell lines expressing BRAK (MC57-BRAK) or mock vector (MC57-MOCK). Fasudil significantly increased BRAK secretion by MC57-BRAK cells in a dose-dependent manner. To determine the effect of fasudil on tumor growth, MC57-BRAK and MC57-MOCK cells were transplanted into wild-type mice. Fasudil treatment suppressed tumor growth only in mice that had received MC57-BRAK cell transplants. These results indicate that fasudil inhibits fibrosarcoma growth by stimulating BRAK secretion and suggests that fasudil therapy might have clinical efficacy.
authors.affiliation: Department of Clinical Care Medicine, Division of Pharmacology and ESR Laboratories, Kanagawa Dental College, Kanagawa, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Miyamoto
authors.forename: Yojiro
authors.initials: Y
authors.lastname: Maehata
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Ozawa
authors.forename: Takeharu
authors.initials: T
authors.lastname: Ikoma
authors.forename: Eiro
authors.initials: E
authors.lastname: Kubota
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Izukuri
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Kato
authors.forename: Ryu-Ichiro
authors.initials: R
authors.lastname: Hata
authors.forename: Masaichi-Chang-il
authors.initials: MC
authors.lastname: Lee
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism*; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C118056:CXCL14 protein, human; C517518:CXCL14 protein, mouse; D019743:Chemokines, CXC; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; C049347:fasudil