Nonsense-mediated mRNA decay inhibition synergizes with MDM2 inhibition to suppress TP53 wild-type cancer cells in p53 isoform-dependent manner

Liu, Ying; Wu, Meng; Zhang, Lili; Wan, Li; Li, Hexin; Zhang, Lanxin; Sun, Gaoyuan; Huang, Wei; Zhang, Junhua; Su, Fei; Tang, Min; Xiao, Fei

doi:10.1038/s41420-022-01190-3

Cited by 7 publications

(6 citation statements)

References 34 publications

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“… 49 P53 was a tumor suppressor and mutated in more than 50% of cancers, transactivating p53 pathway could induce apoptosis and cell-cycle arrest. 50 DNTTIP1 expression was significantly positively correlated with DNA repair, p53 pathway, tumor growth signature, G2M checkpoint, DNA replication, indicating that DNTTIP1 was related to cell cycle and cell repair.…”

Section: Discussionmentioning

confidence: 92%

High Expression of DNTTIP1 Predicts Poor Prognosis in Clear Cell Renal Cell Carcinoma

Wang¹,

Wei-quan²,

Lou³

et al. 2023

PGPM

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Background Invasion and metastasis led to poor prognosis and death of clear cell renal cell carcinoma (ccRCC) patients. The deoxynucleotidyl transferase terminal interacting protein 1 (DNTTIP1) was reported to promote multiple tumor progression. However, there is no research about DNTTIP1 in ccRCC. Methods Kaplan–Meier survival analysis, multivariate analysis demonstrated the prognostic indicator in overall survival (OS) and disease-free survival (DFS) of ccRCC with DNTTIP1 expression in the Cancer Genome Atlas Kidney Clear Cell Carcinoma (TCGA-KIRC). Receiver operator characteristic (ROC) curve analyzed diagnostic ability of DNTTIP1 in TCGA-KIRC and validation dataset. The quantitative real-time polymerase chain reaction (qRT-PCR) detected the DNTTIP1 expression in renal cancer tissues, and the Office of Cancer Clinical Proteomics Research (CPTAC) verified the protein expression of DNTTIP1. Moreover, nomogram predicted the role of DNTTIP1 in ccRCC patient. Single-sample Gene Set Enrichment Analysis (SsGSEA) and GSEA evaluated the pathogenesis role of DNTTIP1 in TCGA-KIRC. Results DNTTIP1 expression was higher in ccRCC tumor tissues. High expression of DNTTIP1 was associated with poor OS (HR = 1.618, P < 0.0001), and poor DFS (HR = 1.789, P < 0.0001). SsGSEA and GSEA showed DNTTIP1 was associated with hypoxia, epithelial-mesenchymal transition (EMT), angiogenesis, G2M checkpoint. DNTTIP1 had a positive correlation with EMT biomarkers in ccRCC, and might be an effective target for ccRCC. Conclusion This study provided that higher expression of DNTTIP1 predicted poor prognosis in ccRCC, and DNTTIP1 might be a novel detection biomarker and therapeutic target of tumor malignant in the future.

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Section: Discussionmentioning

confidence: 92%

High Expression of DNTTIP1 Predicts Poor Prognosis in Clear Cell Renal Cell Carcinoma

Wang¹,

Wei-quan²,

Lou³

et al. 2023

PGPM

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“…Altered RNA metabolism in inflammation and autoimmune diseases; 31 32 mutations in NMD elicit type I IFN responses; 33 inhibition of NMD increases p53, 34 linked to SLE activity 35 via promoting apoptosis; 36 inhibition of p53-dependent apoptosis reverses alveolar haemorrhage in murine lupus. 37…”

Section: Discussionmentioning

confidence: 99%

“… 31 32 Mutations in NMD affecting the quality control of aberrant mRNA mutations may predispose to an autoimmune phenotype via type I IFN signalling. 33 Inhibition of NMD upregulates the tumour suppressor protein p53, 34 which has been correlated with SLE activity, 35 likely through induction of apoptosis, 36 and targeting p53-dependent apoptotic mechanisms was shown effective in treating murine diffuse alveolar haemorrhage. 37 Our finding of reduced NMD pathways in patients not fulfilling the LLDAS or DORIS remission criteria is well in line with the aforementioned evidence, further corroborating the relevance of these targets at the biological level.…”

Section: Discussionmentioning

confidence: 99%

Molecular characterisation of lupus low disease activity state (LLDAS) and DORIS remission by whole-blood transcriptome-based pathways in a pan-European systemic lupus erythematosus cohort

Parodis,

Lindblom,

Barturen

et al. 2024

Ann Rheum Dis

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ObjectivesTo unveil biological milieus underlying low disease activity (LDA) and remission versus active systemic lupus erythematosus (SLE).MethodsWe determined differentially expressed pathways (DEPs) in SLE patients from the PRECISESADS project (NTC02890121) stratified into patients fulfilling and not fulfilling the criteria of (1) Lupus LDA State (LLDAS), (2) Definitions of Remission in SLE remission, and (3) LLDAS exclusive of remission.ResultsWe analysed data from 321 patients; 40.8% were in LLDAS, and 17.4% in DORIS remission. After exclusion of patients in remission, 28.3% were in LLDAS. Overall, 604 pathways differed significantly in LLDAS versus non-LLDAS patients with an false-discovery rate-corrected p (q)<0.05 and a robust effect size (dr)≥0.36. Accordingly, 288 pathways differed significantly between DORIS remitters and non-remitters (q<0.05 and dr≥0.36). DEPs yielded distinct molecular clusters characterised by differential serological, musculoskeletal, and renal activity. Analysis of partially overlapping samples showed no DEPs between LLDAS and DORIS remission. Drug repurposing potentiality for treating SLE was unveiled, as were important pathways underlying active SLE whose modulation could aid attainment of LLDAS/remission, including toll-like receptor (TLR) cascades, Bruton tyrosine kinase (BTK) activity, the cytotoxic T lymphocyte antigen 4 (CTLA-4)-related inhibitory signalling, and the nucleotide-binding oligomerization domain leucine-rich repeat-containing protein 3 (NLRP3) inflammasome pathway.ConclusionsWe demonstrated for the first time molecular signalling pathways distinguishing LLDAS/remission from active SLE. LLDAS/remission was associated with reversal of biological processes related to SLE pathogenesis and specific clinical manifestations. DEP clustering by remission better grouped patients compared with LLDAS, substantiating remission as the ultimate treatment goal in SLE; however, the lack of substantial pathway differentiation between the two states justifies LLDAS as an acceptable goal from a biological perspective.

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“…These MDM2 homo-PROTACs can break down MDM2 proteins without adding additional targets and reducing the possible side effects [25]. As our previous work potently developed selective MDM2 inhibitors of PE-Gylation spirooxindole derivatives derived from spiroindolinone pyrrolidinecarboxamide compound 2 [26][27][28], here, we developed a dimer, spiroindolinone pyrrolidinecarboxamide XR-4, as a potent MDM2-p53 inhibitor. This compound can specifically block MDM2-p53 interaction, downregulate MDM2 protein levels, and inhibit wild-type p53 cancer cell proliferation activity in vitro.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antineoplastic Activity of a Dimer, Spiroindolinone Pyrrolidinecarboxamide

Cui

Wang

et al. 2023

Molecules

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The mutation or function loss of tumour suppressor p53 plays an important role in abnormal cell proliferation and cancer generation. Murine Double Minute 2 (MDM2) is one of the key negative regulators of p53. p53 reactivation by inhibiting MDM2–p53 interaction represents a promising therapeutic option in cancer treatment. Here, to develop more effective MDM2 inhibitors with lower off-target toxicities, we synthesized a dimer, spiroindolinone pyrrolidinecarboxamide XR-4, with potent MDM2-p53 inhibition activity. Western blotting and qRT-PCR were performed to detect the impact of XR-4 on MDM2 and p53 protein levels and p53 downstream target gene levels in different cancers. Cancer cell proliferation inhibition and clonogenic activity were also investigated via the CCK8 assay and colony formation assay. A subcutaneous 22Rv1-derived xenografts mice model was used to investigate the in vivo anti-tumour activity of XR-4. The results reveal that XR-4 can induce wild-type p53 accumulation in cancer cells, upregulate the levels of the p53 target genes p21 and PUMA levels, and then inhibit cancer cell proliferation and induce cell apoptosis. XR-4 can also act as a homo-PROTAC that induces MDM2 protein degradation. Meanwhile, the in vivo study results show that XR-4 possesses potent antitumour efficacy and a favourable safety property. In summary, XR-4 is an interesting spiroindolinone pyrrolidinecarboxamide-derivative dimer with effective p53 activation activity and a cancer inhibition ability.

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Nonsense-mediated mRNA decay inhibition synergizes with MDM2 inhibition to suppress TP53 wild-type cancer cells in p53 isoform-dependent manner

Cited by 7 publications

References 34 publications

High Expression of DNTTIP1 Predicts Poor Prognosis in Clear Cell Renal Cell Carcinoma

High Expression of DNTTIP1 Predicts Poor Prognosis in Clear Cell Renal Cell Carcinoma

Molecular characterisation of lupus low disease activity state (LLDAS) and DORIS remission by whole-blood transcriptome-based pathways in a pan-European systemic lupus erythematosus cohort

Synthesis and Antineoplastic Activity of a Dimer, Spiroindolinone Pyrrolidinecarboxamide

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