New treatment options to battle
hormone-refractory prostate
carcinoma (PC) are a pressing medical need. Chronic
inflammation has been implicated in PC etiology. The pro-inflammatory
cytokines IL-6,
IL-23 and
IL-17 are key mediators to promote growth of PC. Here, we evaluate the potential of immunoproteasome inhibition for anti-inflammatory and direct anti-tumorigenic
therapy of PC. The anti-
tumor effect of immunoproteasome inhibitor
ONX 0914 was tested in mouse and human PC cells and the in vivo therapeutic efficacy of immunoproteasome inhibition was analyzed in transgenic
adenocarcinoma of the mouse prostate (TRAMP) mice in preventive and therapeutic settings and in
castration-resistant (CR)PC after
castration. Inhibition of the immunoproteasome subunit LMP7 induced apoptotic cell death in PC cell lines. In TRAMP mice, ONX 0914-treatment resulted in significant inhibition of PC growth with a decreased frequency of malignant prostatic lesions and inhibition of
metastasis formation. The number of immunosuppressive myeloid cells in PC was greatly reduced in response to
ONX 0914. Thus, immunoproteasome inhibition shows remarkable efficacy against PC progression in vivo and impedes
tumor recurrence in CRPC-TRAMP mice by blocking the immunosuppressive inflammatory response in the tumor microenvironment. In conclusion, we show that the immunoproteasome is a promising
drug target for the treatment of PC.