Expression of the ubiquitin ligase subunit cyclin kinase subunit 1 and its relationship to S-phase kinase protein 2 and p27Kip1 in prostate cancer.

Abstract

Loss of the cell cycle inhibitory protein p27Kip1 in cancer is associated with tumor aggressiveness and poor prognosis in the prostate. The decrease in p27(Kip1) results from increased proteasome dependent degradation, which is mediated by its specific ubiquitin ligase subunits S-phase kinase protein 2 and cyclin dependent kinase subunit 1. S-phase kinase protein 2 was found to be over expressed in aggressive prostate cancers but to our knowledge the role of cyclin dependent kinase subunit 1 in these cancers is unknown. The expression of cyclin dependent kinase subunit 1, S-phase kinase protein 2 and p27Kip1 was examined by immunohistochemistry in tissue sections from 45 patients with prostate cancer. The expression of cyclin dependent kinase subunit 1 was compared to that of S-phase kinase protein 2 and p27Kip1, and patient clinical and histological characteristics. Cyclin dependent kinase subunit 1 expression was strongly associated with S-phase kinase protein 2 expression (r = 0.666, p = 0.001) and inversely with p27Kip1 expression (r = -0.737, p < 0.001). Cyclin dependent kinase subunit 1 over expression was associated with loss of tumor differentiation (r = 0.631, p = 0.001), high serum prostate specific antigen (r = 0.627, p < 0.001) and metastatic disease (p < 0.001). These results suggest that cyclin dependent kinase subunit 1 is involved in p27Kip1 down-regulation and it may have an important causative role in the development of aggressive tumor behavior in prostate cancer.