Site-specific S-nitrosylation of integrin ?6 increases the extent of prostate cancer cell migration by enhancing integrin ?1 association and weakening adherence to laminin-1.

ABSTRACT: The increased mortality in prostate cancer is usually the result of metastatic progression of the disease from the organ-confined location. Among the major events in this progression cascade are enhanced cell migration and loss of adhesion. Moreover, elevated levels of nitric oxide (NO) and inducible nitric oxide synthase (iNOS) found within the tumor microenvironment are hallmarks of progression of this cancer. To understand the role of nitrosative stress in prostate cancer progression, we investigated the effects of NO and iNOS on prostate cancer cell migration and adhesion. Our results indicate that ectopic expression of iNOS in prostate cancer cells increased the extent of cell migration, which could be blocked by selective ITG?6 blocking antibody or iNOS inhibitors. Furthermore, iNOS was found to cause S-nitrosylation of ITG?6 at Cys86 in prostate cancer cells. By comparing the activities of wild-type ITG?6 and a Cys86 mutant, we showed that treatment of prostate cancer cells with NO increased the level of ITG?6 heterodimerization with ITG?1 but not with ITG?4. Finally, S-nitrosylation of ITG?6 weakened its binding to laminin-?1 and weakened the adhesion of prostate cancer cells to laminin-1. In conclusion, S-nitrosylation of ITG?6 increased the extent of prostate cancer cell migration, which could be a potential mechanism of NO- and iNOS-induced enhancement of prostate cancer metastasis.

SUBMITTER: Isaac J 

PROVIDER: S-EPMC3567210 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature