The proteasome inhibitor, bortezomib, induces prostate cancercell death by suppressing the expression of prostate-specific membrane antigen, as well as androgen receptor

Abstract

The progression of primary prostate cancer (PC) is dependent on the androgen receptor (AR) and prostate-specific membrane antigen (PSMA). Furthermore, the growth of PC cells is terminated with the downregulation of both AR and PSMA. In our preliminary experiments, it was also found that bortezomib (BZ; PS-341) that inhibits 26S proteasome activity, acts as a downregulator of both PSMA and AR. In addition to evaluating the effects of BZ on protein expression, the present study evaluated and compared the anticancer effects of BZ on the growth of cells treated with BZ, docetaxel (DOC), or a combination of both. Western blot analysis was used to examine the expression levels of AR and PSMA. The knockdown effect of small interfering RNA (siRNA) and the drugs on the expression of either AR or PSMA was also evaluated. An MTT assay was performed in order to evaluate the inhibitory effects of the drugs on PC cells. The cell cycles were analyzed, and apoptotic cells were detected. The downregulation of AR and PSMA was observed using siRNA specific to AR or PSMA, and the inhibition of PSMA, as well as that of AR severely suppressed the growth of PC cells. The inhibitory effect of BZ alone on PSMA expression was similar to that of both AR- and PSMA-specific siRNA, and this drug also induced the downregulation of AR and PSMA in PC cells. This phenomenon was confirmed even in cells transfected to overexpress PSMA. The apoptosis-promoting effect of BZ on the cells was similar to that observed with BZ plus DOC, and more potent than that of DOC alone. BZ had the same inhibitory effect on the expression of AR and PSMA as did siRNA specific to AR or PSMA. On the whole, the findings of this study indicate that BZ may prove to be a promising chemotherapeutic agent and may be used as a molecularly targeted drug in the treatment of PC.