Castration-resistant prostate cancer (CRPC) is refractory to hormone treatment. This study aims to explore the effect and underlying mechanisms of immunoproteasome inhibition, a novel immunotherapy, on the progression of CRPC.
The immunoproteasome subunit LMP7 was silenced by using gene knockout or inhibited by the epoxyketone inhibitor ONX 0914 in a mouse CRPC tumour graft model and in interferon-γ-pretreated human CRPC cell lines in vitro.
CRPC tissues reveal a significant “tumour-elicited” Th17-type inflammatory response which induces immunoproteasome subunit expression. LMP7 deficiency in host mice or in CRPC tumour grafts had no effect on the “tumour-elicited” Th17-type inflammatory response and tumour progression. However, the selective LMP7 inhibitor ONX 0914 strongly suppressed the “tumour-elicited” Th17-type inflammatory response and CRPC tumour progression. Treatment of wild-type mice receiving LMP7-deficient CRPC tumour grafts with ONX 0914 further suggested that immunoproteasome inhibition prevents CRPC progression through suppressing IL-17-induced angiogenesis and epithelial–mesenchymal transition via inactivation of COX-2/VEGF-A signalling and β-catenin/Snail signalling. Treatment of LMP7-deficient mice receiving wild-type CRPC tumour grafts with ONX 0914 and inhibition of LMP7 in PC3 and 22Rv.1 cells with ONX 0914 showed that immunoproteasome inhibition also prevents CRPC progression through inducing CRPC cell apoptosis via activation of the unfolded protein response.
We define a critical role of the immunoproteasome in CRPC and propose immunoproteasome inhibition as a promising therapeutic approach to suppress CRPC progression.
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Data generated or analysed during this study are included in this published article and its Supplementary Information files or are available from the corresponding author on a reasonable request.
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The authors acknowledge Prof. Marcus Groettrup for his primary conceptual and designation of this work.
This work was supported by the National Natural Science Foundation of China  and the Senior Medical Talents Program of Chongqing for Young and Middle-aged  to JL and by the German Science Foundation (DFG) grant [Nr. GR1517/27-1] to MB and by the Chongqing medical scientific research project (Joint project of Chongqing Health Commission and Science and Technology Bureau) [2021MSXM135] to YPS.
Ethics approval and consent to participate
The study was approved by the Ethics Committee of Chongqing University Cancer Hospital and performed in accordance with the Declaration of Helsinki for human subject protection. No personal information of patients was involved.
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Li, J., Liu, N., Zhou, H. et al. Immunoproteasome inhibition prevents progression of castration-resistant prostate cancer. Br J Cancer (2023). https://doi.org/10.1038/s41416-022-02129-2