Fasudil, a Rho kinase inhibitor, suppresses tumor growth by inducing CXCL14/BRAK in head and neck squamous cell carcinoma.
CXCL14/BRAK (BRAK) is a secreted chemokine with anti-tumor activity, and its expression is suppressed in tumor cells. We previously reported the anti-tumor activity of BRAK in cell lines of head and neck squamous cell carcinoma (HNSCC) and the suppression of BRAK secretion in these cells. BRAK secretion in fibrosarcoma cells is restored by Fasudil, which is a Rho-kinase (ROCK) inhibitor. In this study, we examined the anti-tumor effect of BRAK by evaluating its gene expression and protein secretion in HNSCC cell lines. We found that BRAK mediated the suppressive effect of Fasudil against HNSCC cells. Tumor development in female BALB/cAJclnu/nu mice was suppressed by Fasudil. Also secretion of BRAK protein by tumor cell lines in vitro was significantly stimulated by Fasudil treatment. Similarly, the production of BRAK protein was significantly increased by the addition of Fasudil to cultured tumor cells. Furthermore Fasudil significantly increased BRAK gene expression at the mRNA level in HNSCC cell line. Inhibition of the RhoA/ROCK pathway by siRNAs significantly stimulated BRAK gene expression. These results show that the tumor-suppressive effect of Fasudil was mediated by BRAK, suggesting that Fasudil may therefore be useful for the treatment of HNSCC.
Department of Oral Science, Graduate School, Kanagawa Dental University; Oral Health Science Research Center, Japan.
Chihiro
C
Miyamoto
Yojiro
Y
Maehata
Kazuhiko
K
Motohashi
Shigeyuki
S
Ozawa
Takeharu
T
Ikoma
Kouki
K
Hidaka
Satoko
S
Wada-Takahashi
Shun-Suke
SS
Takahashi
Fumihiko
F
Yoshino
Ayaka
A
Yoshida
Eiro
E
Kubota
Ryu-Ichiro
R
Hata
Masaichi-Chang-il
MC
Lee
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D019743:Chemokines, CXC / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D000077195:Squamous Cell Carcinoma of Head and Neck; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
C118056:CXCL14 protein, human; D019743:Chemokines, CXC; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil