Fasudil, a Rho kinase inhibitor, suppresses tumor growth by inducing CXCL14/BRAK in head and neck squamous cell carcinoma

Abstract

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.

CXCL14 suppresses human papillomavirus-associated head and neck cancer through antigen-specific CD8+ T-cell responses by upregulating MHC-I expression

“…CXCL14 may also induce tumor suppression in other cancers beyond HPV-positive cancers, as CXCL14 expression is downregulated in several cancers including renal and gastric cancers [18,19]. Indeed, restoration of CXCL14 expression triggers tumor suppression in lung and colorectal cancers, as well as HNC [44,48,49]. In addition, CXCL14 could be used to treat HPV-positive premalignant lesions for cancer prevention.…”

CXCL14 as an emerging immune and inflammatory modulator

“…In head and neck squamous cell carcinoma (HNSCC), CXCL14 expression and secretion and its anti-tumor effect is negatively regulated by RhoA/ROCK pathway. Therefore Fasudil, ROCK-specific inhibitor can stimulate CXCL14 expression [ 37 ]. In clear cell renal cell carcinoma, S100A6 (Calcyclin), as an oncogenic protein, negatively regulates CXCL14 expression, and knockdown of S100A6 promotes CXCL14-mediated apoptosis and promotes tumour progression [ 38 ].…”

Bioinformatics analysis of the role of CXC ligands in the microenvironment of head and neck tumor

“…Low CXCL2, 3, and 12 mRNA levels predicted high RFS, suggesting that they play important regulatory roles in promoting tumor recurrence. Although few studies have investigated CXCL14, high CXCL14 expression has been found to suppress tumor growth in HNSC [ 41 ]. We found that CXCL14 is associated with tumor stage, OS, and RFS, suggesting that it could be an important target for treating HNSC.…”