Inhibition of endothelial nitric oxide synthase in cholangiocarcinoma cell lines - a new strategy for therapy.

The isoform of nitric oxide synthase (NOS) found in endothelial cells (eNOS) plays a crucial role in vasodilation. We recently reported the activation of eNOS in cholangiocarcinoma (CCA) tissues and cell lines. Moreover, we also reported that the abundance of eNOS and phosphorylated eNOS (p-eNOS), as well as its upstream regulator proteins, is significantly associated with the metastatic status of CCA patients. However, the function of eNOS in CCA progression has not been addressed. Therefore, the present study aimed to investigate the function of eNOS involved in the migration and invasion ability of CCA cell lines. The results reveal that eNOS activation significantly increases migration and invasion ability of CCA cells the up-regulation of phosphorylated vasodilator-stimulated protein (p-VASP). A combination treatment with recombinant human vascular endothelial growth factor C and eNOS inhibitor (-nitro-l-arginine methyl ester hydrochloride) resulted in the down-regulation of p-VASP, as well as a decreased migration and invasion ability of the CCA cell line. Thus, this work suggests that eNOS can serve as an attractive target to inhibit the progression of CCA.