Notch Signaling Regulates Mitochondrial Metabolism and NF-κB Activity in Triple-Negative Breast Cancer Cells via IKKα-Dependent Non-canonical Pathways

Hossain, Fokhrul; Sissi, Claudia; Uçar, Deniz A.; Peng, Yin; Matossian, Margarite D.; Wyczechowska, Dorota; Crabtree, Judy S.; Zabaleta, Jovanny; Morello, Silvana; Valle, Luis Del; Burow, Matthew E.; Collins‐Burow, Bridgette M.; Pannuti, Antonio; Minter, Lisa M.; Golde, Todd E.; Osborne, Barbara A.; Miele, Lucio

doi:10.3389/fonc.2018.00575

Cited by 76 publications

(57 citation statements)

References 96 publications

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“…Besides, a recent study has also shown that sphingosine-1-phosphate (S1P) promotes CSC expansion via S1P receptor 3 and subsequent Notch1 activation in estrogen receptor (ER)-positive breast cancer cells 45 , suggesting that activation of Notch1 signaling in breast CSCs might be mediated through both Notch ligand-dependent and -independent pathways. Moreover, it is important to note that, in addition to the canonical nuclear signaling, Notch1 also drives non-canonical, cytoplasmic and mitochondrial signals in TNBC stem cells [46][47][48][49] , highlighting the generation of cell contextdependent diversity in the Notch1 signaling output. Nevertheless, the cause of the expression of Notch ligands in tumor perivascular niche is still unclear.…”

Section: Discussionmentioning

confidence: 99%

Jagged1-Notch1-deployed tumor perivascular niche promotes breast cancer stem cell phenotype through Zeb1

et al. 2020

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Zinc finger E-box binding homeobox 1 (Zeb1) has been demonstrated to participate in the acquisition of the properties of cancer stem cells (CSCs). However, it is largely unknown how signals from the tumor microenvironment (TME) contribute to aberrant Zeb1 expression. Here, we show that Zeb1 depletion suppresses stemness, colonization and the phenotypic plasticity of breast cancer. Moreover, we demonstrate that, with direct cell-cell contact, TME-derived endothelial cells provide the Notch ligand Jagged1 (Jag1) to neighboring breast CSCs, leading to Notch1-dependent upregulation of Zeb1. In turn, ectopic Zeb1 in tumor cells increases VEGFA production and reciprocally induces endothelial Jag1 in a paracrine manner. Depletion of Zeb1 disrupts this positive feedback loop in the tumor perivascular niche, which eventually lessens tumor initiation and progression in vivo and in vitro. In this work, we highlight that targeting the angiocrine Jag1-Notch1-Zeb1-VEGFA loop decreases breast cancer aggressiveness and thus enhances the efficacy of antiangiogenic therapy.

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Section: Discussionmentioning

confidence: 99%

Jagged1-Notch1-deployed tumor perivascular niche promotes breast cancer stem cell phenotype through Zeb1

et al. 2020

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“…Notch family proteins integrate with a range of signaling cascades that underlie pleiotropic outcomes of Notch signaling [15][16][17] . Here we provide evidence for spatial regulation of Notch4 signaling and its integration with a signaling cascade mediating protection from genomic damage.…”

Section: Discussionmentioning

confidence: 99%

“…Ligand-activated Notch undergoes a series of proteolytic cleavages, releasing the intracellular domain (Notch4 intracellular domain (NIC), which generally localizes to the nucleus [8][9][10] and complexes with cofactors recombination signal-binding protein-Jκ (RBPj-κ) and Mastermind like, to induce transcription of various genes 11,12 . Apart from this core canonical pathway, there are several reports of atypical ligand-independent and non-nuclear Notch signaling in diverse systems [13][14][15][16][17] .…”

Section: Introductionmentioning

confidence: 99%

Nucleolar localization of the Notch4 intracellular domain underpins its regulation of the cellular response to genotoxic stressors

Saini

Sarin

2020

Cell Death Discov.

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Cell survival is one of the many cellular processes regulated by Notch family of proteins. A comparison of human breast cancer cell lines, which differ in the levels of endogenous Notch4, implicated the protein in regulating susceptibility to apoptosis triggered by genomic damage. In agreement with this observation, increased susceptibility to genotoxic damage was observed following siRNA ablations of Notch4 in two breast cancer cell lines. Further, overexpressing Notch4 intracellular domain (NIC4) tagged to GFP (NIC4-GFP), protected cells from apoptosis triggered by genotoxic drugs. In cells immune-stained for endogenous Notch4, protein was detected in the nucleolus and nucleoplasm, which was also confirmed by the co-localization of NIC4-GFP with RFP-tagged nucleolar proteins in breast cancer cells or the unrelated HEK cell line. Linking functional outcomes to nucleolar localization, NIC4-GFP protection from apoptosis, required the nucleolar proteins Nucleolin and Fibrillarin. Consistently, immunoprecipitation analysis revealed associations between nucleolar proteins-Nucleolin and Nucleophosmin-and Notch4. Microscopybased biophysical analysis of live cells showed that nucleolar and nucleoplasmic pools of NIC4-GFP are mobile, with some sequestration of nucleolar NIC4-GFP pools. A nucleolar excluded form, NIC4_3RA-GFP, generated by sitedirected mutagenesis of the nucleolar localization sequence in NIC4, could not protect from apoptosis triggered by genotoxic stressors. However, transcriptional activity or protection from apoptosis triggered by endoplasmic stress was comparable in cells expressing NIC4_3RA-GFP or NIC4-GFP. Together, the data show that nucleolar localization of NIC4 is critical for the regulation of genomic damage and may be uncoupled from its activities in the nucleoplasm. This study identifies intrinsic features of NIC4 that regulate signaling outcomes activated by the receptor by controlling its spatial localization.

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“…For example, Notch signaling is a key method to regulate the survival of CSCs in triple negative breast cancer. Treatment of triple-negative breast cancer with PI3K or mTORC1/2 inhibitors will produce drug-resistant Notch-dependent CSCs [40] . Most tumors are affected by EMT, the process of obtaining mesenchymal features from epithelial cells, during tumor progression.…”

Section: Discussionmentioning

confidence: 99%

LncRNA MONC Suppresses the Malignant Phenotype of Endometrial Cancer Stem Cells by Regulating the MiR-636/GLCE Axis

Y¹,

Huo²,

He³

et al. 2020

Preprint

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Background: Emerging evidence shows that abnormal expression of long non-coding RNA is involved in the occurrence and development of various tumors. LncRNA MONC is abnormally expressed in head and neck squamous cell carcinoma (HNSCC), lung cancer, colorectal cancer, and acute megakaryocytic leukemia, but the biological function and potential regulatory mechanism of MONC in endometrial cancer stem cells (ECSCs) and endometrial cancer cells (ECCs) have not been studied. In this study, we aimed to explore the tumor suppressive effect and mechanism of MONC in regulating ECSCs and ECCs. Methods: The expression of genes was detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The expression of proteins was detected by Western blot. The interplay of LncRNA-miRNA-mRNA was verified using the luciferase assay. The growth rate of ECSC spheroids was detected by sphere formation assay. Cell proliferation was detected by CCK-8 assay. The cell invasion was detected by transwell invasion assay. Cell cycle was detected by Cell cycle analysis.Cell apoptosis was detected by the Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) double-staining assay. Animal study was conducted to evaluate the effect of MONC combined with miR-636 on tumor growth in vivo. Results: Low MONC expression in endometrial carcinoma (EC), which directly inhibits the malignant biological behavior of ECSCs and ECCs by directly inhibiting miR-636. Simultaneously, miR-636 may indirectly reduce the expression of MONC. Down-regulation of miR-636 may promote GLCE expression by targeting the 3'-untranslated region (UTR) of the downstream gene GLCE, thereby inhibiting the progression of ECSCs. MONC combined with miR-636 inhibited the Notch signaling pathway and tumor epithelial-to-mesenchymal transition (EMT) process. In addition, we verified the tumor suppressive effect of MONC in nude mice, miR-636 can rescue the tumor suppressive effect of overexpressing MONC, and this effect is more obvious in ECSC. Conclusion: MONC inhibits the malignant phenotypes of ECSCs and ECCs by regulating the miR-636/GLCE axis. The MONC/miR-636/GLCE axis may provide novel treatment avenues for human EC.

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Notch Signaling Regulates Mitochondrial Metabolism and NF-κB Activity in Triple-Negative Breast Cancer Cells via IKKα-Dependent Non-canonical Pathways

Cited by 76 publications

References 96 publications

Jagged1-Notch1-deployed tumor perivascular niche promotes breast cancer stem cell phenotype through Zeb1

Jagged1-Notch1-deployed tumor perivascular niche promotes breast cancer stem cell phenotype through Zeb1

Nucleolar localization of the Notch4 intracellular domain underpins its regulation of the cellular response to genotoxic stressors

LncRNA MONC Suppresses the Malignant Phenotype of Endometrial Cancer Stem Cells by Regulating the MiR-636/GLCE Axis

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