niraparib and Adenocarcinoma

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.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Atlases as Topic; bcl-2-Associated X Protein; 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