Site-specific S-nitrosylation of Integrin α6 Increases Prostate Cancer Cell Migration by Increasing Integrin β1 Association and Reducing Adherence to Laminin-1

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 increased 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 for this cancer. To understand the role of nitrosative stress in prostate cancer progression, the effects of NO/iNOS on prostate cancer cell migration and adhesion were investigated here. Our results indicate that ectopic expression of iNOS in prostate cancer cells increased cell migration, which could be blocked by selective ITGα6- blocking antibody or iNOS-inhibitors. Furthermore, iNOS was found to cause S-nitrosylation of ITGα6 at Cys86 in prostate cancer cells. By comparing the activities of the wild-type ITGα6 with a Cys86 mutant, we showed that treatment of prostate cancer cells with NO increased ITGα6 heterodimerization with ITGβ1, but not with ITGβ4. Finally, S-nitrosylation of ITGα6 decreased its binding to laminin-β1, and reduced the adhesion of prostate cancer cells to laminin-1. In conclusion, S-nitrosylation of ITGα6 increased prostate cancer cell migration, which could be a potential mechanism of NO/iNOS–induced enhancement of prostate cancer metastasis.