Notch4 inhibition reduces migration and invasion and enhances sensitivity to docetaxel by inhibiting Akt/fascin in pancreatic cancer cells

Qian, Cheng; Chen, Yiyi; Zhang, Xin; Liu, Fu‐Qiang; Yue, Tingting; Ye, Bei; Yao, Jun

doi:10.3892/ol.2016.5097

Cited by 15 publications

(16 citation statements)

References 31 publications

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“…In another model of breast cancer—MCF7 cells—increased expression of Notch4 elicited EMT and invasiveness [ 70 ]. Notch4 is also upregulated in pancreatic cancer cell lines compared to non-transformed cells and its inhibition impairs viability, migration, and invasion [ 71 ]. Notch4 activity was also associated with EMT gene expression signature in melanoma cells and held responsible for increased metastasis [ 72 ].…”

Section: Diversity Of Notch Signaling Activities In Cancermentioning

confidence: 99%

Taming the Notch Transcriptional Regulator for Cancer Therapy

2018

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Notch signaling is a highly conserved pathway in all metazoans, which is deeply involved in the regulation of cell fate and differentiation, proliferation and migration during development. Research in the last decades has shown that the various components of the Notch signaling cascade are either upregulated or activated in human cancers. Therefore, its downregulation stands as a promising and powerful strategy for cancer therapy. Here, we discuss the recent advances in the development of small molecule inhibitors, blocking antibodies and oligonucleotides that hinder Notch activity, and their outcome in clinical trials. Although Notch was initially identified as an oncogene, later studies showed that it can also act as a tumor suppressor in certain contexts. Further complexity is added by the existence of numerous Notch family members, which exert different activities and can be differentially targeted by inhibitors, potentially accounting for contradictory data on their therapeutic efficacy. Notably, recent evidence supports the rationale for combinatorial treatments including Notch inhibitors, which appear to be more effective than single agents in fighting cancer.

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Section: Diversity Of Notch Signaling Activities In Cancermentioning

confidence: 99%

Taming the Notch Transcriptional Regulator for Cancer Therapy

2018

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“…Notch4 signaling promotes breast cancer cell survival in response to diverse treatment modalities [18][19][20] and is implicated in poor prognosis and high risk of relapse in breast cancer patients 21 . Notch4 signaling regulates susceptibility to cell death in human B cell acute lymphoblastic leukemia 1 , endothelial 3 , as well as cells of pancreatic origin 22 among others. Hence, while many studies have correlated Notch4 signaling with resistance to cell death, in-depth analysis of molecular details underlying Notch4-mediated anti-apoptotic activity have not been undertaken.…”

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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“…Furthermore, PC cells upregulate Notch4 that was linked to chemotherapy resistance. Indeed, downregulation of Notch4 using siRNA sensitized PC cells to docetaxel [ 35 ].…”

Section: Introductionmentioning

confidence: 99%

Leptin-Notch axis impairs 5-fluorouracil effects on pancreatic cancer

Harbuzariu

Gonzalez-Perez

2018

Oncotarget

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5-FU chemotherapy is a current strategy to treat pancreatic cancer (PC), but unfortunately chemoresistance is eventually developed in most patients. Obesity is a risk factor for PC that could affect 5-FU effectiveness through the adipokine leptin, which is a known proliferation, survival factor and Notch inducer. We investigated whether leptin signaling affects 5-FU cytotoxicity on PC. To this end, tumorspheres developed from BxPC-3 and MiaPaCa-2 PC cells were treated with 5-FU, leptin, inhibitors for Notch (DAPT) and leptin signaling (IONP-LPrA2) and ATP-binding cassette of proteins (Probenecid). Leptin treatment decreased 5-FU cytotoxicity, and increased cell proliferation, colony forming ability, stem cell, pluripotency, EMT markers, drug efflux proteins (ABCC5, ABCC11) and Notch. In addition, leptin reduced the 5-FU effects on apoptosis by decreasing pro-apoptotic (Bax, Caspase-3 activation and PARP degradation) and increasing anti-apoptotic factors (RIP and Bcl-XL). Leptin's effects on PC tumorspheres treated with 5-FU were reduced by IONP-LPrA2 and were mainly Notch signaling- dependent and more evident in MiaPaCa-2-derived tumorspheres. Present results suggest that leptin could impair 5-FU cytotoxicity and promote chemoresistance. Therefore, targeting the leptin-Notch axis could be a novel way to improve 5-FU therapy for PC patients, especially in obesity context.

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Notch4 inhibition reduces migration and invasion and enhances sensitivity to docetaxel by inhibiting Akt/fascin in pancreatic cancer cells

Cited by 15 publications

References 31 publications

Taming the Notch Transcriptional Regulator for Cancer Therapy

Taming the Notch Transcriptional Regulator for Cancer Therapy

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

Leptin-Notch axis impairs 5-fluorouracil effects on pancreatic cancer

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