NPRL2 reduces the niraparib sensitivity of castration-resistant prostate cancer via interacting with UBE2M and enhancing neddylation.
In this study, we explored the regulatory effects of nitrogen permease regulator 2-like (NPRL2) on niraparib sensitivity, a PARP inhibitor (PARPi) in castrate-resistant prostate cancer (CRPC). Data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) program were retrospectively examined. Gene-set enrichment analysis (GSEA) was conducted between high and ... low NRPL2 expression prostate adenocarcinoma (PRAD) cases in TCGA. CCK-8 assay, Western blot analysis of apoptotic proteins, and flow cytometric analysis of apoptosis were applied to test niraparib sensitivity. Immunofluorescent (IF) staining and co-immunoprecipitation (co-IP) were conducted to explore the proteins interacting with NPRL2. Results showed that the upregulation of a canonical protein-coding transcript of NPRL2 (ENST00000232501.7) is associated with an unfavorable prognosis. Bioinformatic analysis predicts a physical interaction between NPRL2 and UBE2M, which is validated by a following Co-IP assay. This interaction increases NPRL2 stability by reducing polyubiquitination and proteasomal degradation. Depletion of NPRL2 or UBE2M significantly increases the niraparib sensitivity of CRPC cells and enhances niraparib-induced tumor growth inhibition in vivo. NPRL2 cooperatively enhances UBE2M-mediated neddylation and facilitates the degradation of multiple substrates of Cullin-RING E3 ubiquitin ligases (CRLs). In conclusion, this study identified a novel NPRL2-UBE2M complex in modulating neddylation and niraparib sensitivity of CRPC cells. Therefore, targeting NPRL2 might be considered as an adjuvant strategy for PARPi therapy.
Mesh Terms:
Adenocarcinoma, Animals, Antineoplastic Agents, Atlases as Topic, Caspase 3, Cell Line, Tumor, Cell Movement, Cell Proliferation, Databases, Genetic, Gene Expression Regulation, Neoplastic, Humans, Indazoles, Male, Mice, Mice, Inbred BALB C, Mice, Nude, NEDD8 Protein, Piperidines, Prostatic Neoplasms, Castration-Resistant, Protein Processing, Post-Translational, Proto-Oncogene Proteins c-bcl-2, RNA, Small Interfering, Signal Transduction, Survival Analysis, Tumor Suppressor Proteins, Ubiquitin-Conjugating Enzymes, Xenograft Model Antitumor Assays, bcl-2-Associated X Protein
Adenocarcinoma, Animals, Antineoplastic Agents, Atlases as Topic, Caspase 3, Cell Line, Tumor, Cell Movement, Cell Proliferation, Databases, Genetic, Gene Expression Regulation, Neoplastic, Humans, Indazoles, Male, Mice, Mice, Inbred BALB C, Mice, Nude, NEDD8 Protein, Piperidines, Prostatic Neoplasms, Castration-Resistant, Protein Processing, Post-Translational, Proto-Oncogene Proteins c-bcl-2, RNA, Small Interfering, Signal Transduction, Survival Analysis, Tumor Suppressor Proteins, Ubiquitin-Conjugating Enzymes, Xenograft Model Antitumor Assays, bcl-2-Associated X Protein
Exp Cell Res
Date: Dec. 15, 2020
PubMed ID: 33905671
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