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Translational Therapeutics

Immunoproteasome inhibition prevents progression of castration-resistant prostate cancer

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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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Fig. 1: “Tumour-elicited” Th17-type inflammatory response in castration-resistant prostate cancer (CRPC) tissues.
Fig. 2: The immunoproteasome is expressed in castration-resistant prostate cancer (CRPC) tissues.
Fig. 3: Immunoproteasome inhibition by ONX 0914 suppresses the “tumour-elicited” Th17-type inflammatory response in castration-resistant prostate cancer (CRPC) tissues.
Fig. 4: Immunoproteasome inhibition by ONX 0914 prevents the progression of castration-resistant prostate cancer (CRPC).
Fig. 5: ONX 0914 activates the unfolded protein response and induces apoptosis of castration-resistant prostate cancer (CRPC) cells.
Fig. 6: Immunoproteasome inhibition by ONX 0914 suppresses angiogenesis signalling in castration-resistant prostate cancer (CRPC) tissues.
Fig. 7: Immunoproteasome inhibition by ONX 0914 suppresses epithelial–mesenchymal transition of castration-resistant prostate cancer (CRPC) cells.

Data availability

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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Acknowledgements

The authors acknowledge Prof. Marcus Groettrup for his primary conceptual and designation of this work.

Funding

This work was supported by the National Natural Science Foundation of China [81870304] and the Senior Medical Talents Program of Chongqing for Young and Middle-aged [20190829] 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.

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Contributions

JL and MB were in charge of conceptual and experimental design, data interpretation and manuscript refinement. NL and HZ analysed data and wrote the article. PX, YS, XT and YL performed the experiments.

Corresponding authors

Correspondence to Jun Li or Michael Basler.

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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

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