Targeting Notch4 in Cancer: Molecular Mechanisms and Therapeutic Perspectives

Xiu, Mengxi; Zeng, Xiaohong; Shan, Renfeng; Wen, Wu; Li, Jianfeng; Wan, Renhua

doi:10.2147/cmar.s315511

Cited by 18 publications

(13 citation statements)

References 78 publications

(205 reference statements)

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“…NOTCH4: The functions of NOTCH4 differ in different types of cancer. The overexpression of NOTCH4 is regarded as a poor prognosis marker in some scenarios 618 , while in others, it is considered a favorable marker 619 . There are no mature drugs targeting NOTCH4.…”

Section: Notch-targeted Therapiesmentioning

confidence: 99%

Notch signaling pathway: architecture, disease, and therapeutics

Zhou

Wanling

Long

et al. 2022

Sig Transduct Target Ther

459

255

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The NOTCH gene was identified approximately 110 years ago. Classical studies have revealed that NOTCH signaling is an evolutionarily conserved pathway. NOTCH receptors undergo three cleavages and translocate into the nucleus to regulate the transcription of target genes. NOTCH signaling deeply participates in the development and homeostasis of multiple tissues and organs, the aberration of which results in cancerous and noncancerous diseases. However, recent studies indicate that the outcomes of NOTCH signaling are changeable and highly dependent on context. In terms of cancers, NOTCH signaling can both promote and inhibit tumor development in various types of cancer. The overall performance of NOTCH-targeted therapies in clinical trials has failed to meet expectations. Additionally, NOTCH mutation has been proposed as a predictive biomarker for immune checkpoint blockade therapy in many cancers. Collectively, the NOTCH pathway needs to be integrally assessed with new perspectives to inspire discoveries and applications. In this review, we focus on both classical and the latest findings related to NOTCH signaling to illustrate the history, architecture, regulatory mechanisms, contributions to physiological development, related diseases, and therapeutic applications of the NOTCH pathway. The contributions of NOTCH signaling to the tumor immune microenvironment and cancer immunotherapy are also highlighted. We hope this review will help not only beginners but also experts to systematically and thoroughly understand the NOTCH signaling pathway.

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Section: Notch-targeted Therapiesmentioning

confidence: 99%

Notch signaling pathway: architecture, disease, and therapeutics

Zhou

Wanling

Long

et al. 2022

Sig Transduct Target Ther

459

255

View full text Add to dashboard Cite

show abstract

“…NOTCH4 expression was significantly higher in breast cancer patients compared to normal (Figure 4). Most studies suggested that NOTCH4 is abnormally overexpressed during cancer development and is involved in the regulation of several tumor-cell behaviours, mainly in stem cell-like self-renewal, epithelial-mesenchymal transition (EMT), radio-/chemo resistance and angiogenesis (Wu et al 2014;Lin et al 2016;Wu et al 2018;Shaik et al 2020;Xiu et al 2021). In contrast to C-JUN and NOTCH4, the expression of CTNND1 was significantly lower in breast cancer patients (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

“…Targeting C-JUN in adenocarcinomic human alveolar basal epithelial cells (A549) exhibits antiangiogenic activity in vitro and in vivo through exosome/miRNA-494-3p/PTEN signalling pathway (Shao et al 2021). Overexpression of NOTCH4 is reported in cancer development and is involved in EMT, angiogenesis and even radio-/ chemo resistance (Xiu et al 2021). In breast cancer, RNA-binding protein (RBP) DCAF13 induces NOTCH4 overexpression by inhibiting the activation of the E3 ubiquitin-protein ligase DTX3 that prevents NOTCH4 degradation (Liu et al 2020).…”

Section: Discussionmentioning

confidence: 99%

Annonacin and Squamocin Conjugation with Nanodiamond Alters Metastatic Marker Expression in Breast Cancer Cell Line

Dewi,

Sri Puji Astuti Wahyuningsih,

Adelah Putri Milenia Sari

et al. 2023

HAYATI J Biosci

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Breast cancer can perform metastasis to distant organs and cause more than 90% of malignancy-related deaths. The anti-metastasis potency of nanodiamond-conjugated annonacin and squamocin against MCF-7 cells is currently studied. First, IC50 determination of both free annonacin and squamocin to evaluate their potency as cytotoxic agents. Upon getting the IC50 value, both compounds are conjugated into nanodiamonds. Drug loading efficiencies of nanodiamond-conjugated annonacin and squamocin are 88.9% and 89.1%, respectively. Meanwhile, the ND-annonacin and ND-squamocin complex size is 150-300 nm based on SEM imaging. Subsequently, cell viability assessment of MCF-7 was performed with six cohort designs, namely, K (control cell), AN (annonacin), SQ (squamocin), NDAN (nanodiamond-conjugated annonacin), and NDSQ (nanodiamond-conjugated squamocin). Both IC50 and cell viability are assessed by MTT assay after 24 h incubation. All cohorts also underwent gene expression analysis subject to the metastasis markers CTNND1 (catenin delta 1), NOTCH4, and C-JUN. Here, the IC50 of both free annonacin (4.52 µg/ml) and squamocin (10.03 µg/ml) are more than IC50 of potent anticancer (< 4 µg/ml) for pure compounds. However, nanodiamond conjugation to both compounds can decrease cell viability better than free compounds. Compared to K, nanodiamond-conjugated annonacin and squamocin significantly decreases cell viability after 24 h incubation. Bioinformatics analysis confirmed significant pro-metastasis (C-JUN and NOTCH4) upregulation and anti-metastasis (CTNND1) downregulation in tumors compared to normal. Recent findings demonstrated that nanodiamond-conjugated annonacin can significantly upregulate CTNND1 and significantly downregulate C-JUN and NOTCH4. Even so, nanodiamond-conjugated squamocin upregulate CTNND1 but not significantly and significantly downregulate C-JUN and NOTCH4.

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“…Notch4 signaling not just affects tumor cell biological behaviors but also is responsible for tumor angiogenesis ( Xiu et al, 2021 ). Interestingly, our data demonstrated a similar result that Notch4 showed positive staining both in tumor cells and endothelial cells, suggesting Notch4 may play dual roles respectively in tumor cells and endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Development and validation of an immune infiltration/tumor proliferation-related Notch3 nomogram for predicting survival in patients with primary glioblastoma

et al. 2023

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Background: Notch receptors (Notch 1/2/3/4), the critical effectors of the Notch pathway, participate in the tumorigenesis and progression of many malignancies. However, the clinical roles of Notch receptors in primary glioblastoma (GBM) have not been fully elucidated.Methods: The genetic alteration-related prognostic values of Notch receptors were determined in the GBM dataset from The Cancer Genome Atlas (TCGA). Two GBM datasets from TCGA and Chinese Glioma Genome Atlas (CGGA) were used to explore the differential expression between Notch receptors and IDH mutation status, and GBM subtypes. The biological functions of Notch Receptors were explored by Gene Ontology and KEGG analysis. The expression and prognostic significance of Notch receptors were determined in the TCGA and CGGA datasets and further validated in a clinical GBM cohort by immunostaining. A Notch3-based nomogram/predictive risk model was constructed in the TCGA dataset and validated in the CGGA dataset. The model performance was evaluated by receiver operating curves, calibration curves, and decision curve analyses. The Notch3-related phenotypes were analyzed via CancerSEA and TIMER. The proliferative role of Notch3 in GBM was validated in U251/U87 glioma cells by Western blot and immunostaining.Results: Notch receptors with genetic alterations were associated with poor survival of GBM patients. Notch receptors were all upregulated in GBM of TCGA and CGGA databases and closely related to the regulation of transcription, protein-lysine N-methyltransferase activity, lysine N-methyltransferase activity, and focal adhesion. Notch receptors were associated with Classical, Mesenchymal, and Proneural subtypes. Notch1 and Notch3 were closely correlated with IDH mutation status and G-CIMP subtype. Notch receptors displayed the differential expression at the protein level and Notch3 showed a prognostic significance in a clinical GBM cohort. Notch3 presented an independent prognostic role for primary GBM (IDH1 mutant/wildtype). A Notch3-based predictive risk model presented favorable accuracy, reliability, and net benefits for predicting the survival of GBM patients (IDH1 mutant/wildtype and IDH1 wildtype). Notch3 was closely related to immune infiltration (macrophages, CD4+ T cells, and dendritic cells) and tumor proliferation.Conclusion: Notch3-based nomogram served as a practical tool for anticipating the survival of GBM patients, which was related to immune-cell infiltration and tumor proliferation.

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Targeting Notch4 in Cancer: Molecular Mechanisms and Therapeutic Perspectives

Cited by 18 publications

References 78 publications

Notch signaling pathway: architecture, disease, and therapeutics

Notch signaling pathway: architecture, disease, and therapeutics

Annonacin and Squamocin Conjugation with Nanodiamond Alters Metastatic Marker Expression in Breast Cancer Cell Line

Development and validation of an immune infiltration/tumor proliferation-related Notch3 nomogram for predicting survival in patients with primary glioblastoma

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