Notch3 Targeting: A Novel Weapon against Ovarian Cancer Stem Cells

Ceccarelli, Simona; Megiorni, Francesca; Bellavia, Diana; Marchese, Cinzia; Screpanti, Isabella; Checquolo, Saula

doi:10.1155/2019/6264931

Cited by 23 publications

(22 citation statements)

References 70 publications

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“…Several elements of the Notch pathway were markedly down-regulated and further experimental validation suggested that this downregulation was not consequence but rather a contributor to the senescence program activated by BMS. Notch signaling plays a crucial role during embryonic development and cancer 26 , and its inhibition has been proposed as a potential anti-cancer therapy 36,37 In our hands, activation of the pathway using a recombinant ligand abrogated the pro-senescence effect of BMS. This finding can be highly relevant since the Notch pathway may play a role in the pathogenesis of RA.…”

Section: Discussionmentioning

confidence: 75%

Therapeutic senescence via GPCR activation in synovial fibroblasts facilitates resolution of arthritis

et al. 2020

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Rheumatoid arthritis affects individuals commonly during the most productive years of adulthood. Poor response rates and high costs associated with treatment mandate the search for new therapies. Here we show that targeting a specific G-protein coupled receptor promotes senescence in synovial fibroblasts, enabling amelioration of joint inflammation. Following activation of the melanocortin type 1 receptor (MC 1), synovial fibroblasts acquire a senescence phenotype characterized by arrested proliferation, metabolic reprogramming and marked gene alteration resembling the remodeling phase of wound healing, with increased matrix metalloproteinase expression and reduced collagen production. This biological response is attained by selective agonism of MC 1 , not shared by non-selective ligands, and dependent on downstream ERK1/2 phosphorylation. In vivo, activation of MC 1 leads to anti-arthritic effects associated with induction of senescence in the synovial tissue and cartilage protection. Altogether, selective activation of MC 1 is a viable strategy to induce cellular senescence, affording a distinct way to control joint inflammation and arthritis.

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Section: Discussionmentioning

confidence: 75%

Therapeutic senescence via GPCR activation in synovial fibroblasts facilitates resolution of arthritis

et al. 2020

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“…The above data represent the mean ± SD of three independent experiments. ***, P < 0.001; **, P < 0.01; *, P < 0.05, t test Although c-Kit has been reported to collaborate with Notch signaling in regulating multiple cellular functions [45][46][47], it is unclear whether c-Kit can regulate or activate Notch3, which plays an important role in CSC [34,35,48,49] and high-grade ovarian serous carcinoma [50][51][52][53]. In our study, we found that c-Kit, Notch3 and raft-phospho-PHB protein expression were enhanced in our generated metastatic phenotypes of SKOV3 cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Since c-Kit and Notch3 have been reported to play a role in the regulation of ovarian CSCs [19,34,35] and CSC-driven metastasis [36,37], we examined their expression in these different phenotypes of SKOV3GL cells. Our results showed that c-Kit, full-length (FL) Notch3 and membrane-tethered Notch3 fragment (NTM) expression were all significantly increased in SKOV3GL-G3 and SKOV3GL-G4 cells (Fig.…”

Section: Metastatic Phenotypes Of Skov3 In Xenograft Murine Ascites Smentioning

confidence: 99%

A novel c-Kit/phospho-prohibitin axis enhances ovarian cancer stemness and chemoresistance via Notch3—PBX1 and β-catenin—ABCG2 signaling

et al. 2020

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Background: The underlying mechanism involved in ovarian cancer stemness and chemoresistance remains largely unknown. Here, we explored whether the regulation of c-Kit and plasma membrane prohibitin (PHB) affects ovarian cancer stemness and chemotherapy resistance.Methods: Mass spectrum analysis and an in vitro kinase assay were conducted to examine the phosphorylation of PHB at tyrosine 259 by c-Kit. The in vitro effects of c-Kit on membrane raft-PHB in ovarian cancer were determined using tissue microarray (TMA)-based immunofluorescence, western blotting, immunoprecipitation, colony and spheroid formation, cell migration and cell viability assays. In vivo tumor initiation and carboplatin treatment were conducted in nude mice.Results: We found that c-Kit and PHB colocalized in the raft domain and were positively correlated in human ovarian serous carcinoma. c-Kit interacted with PHB and facilitated the phosphorylation of PHB at tyrosine 259 (phospho-PHB Y259 ) in the membrane raft to enhance ovarian cancer cell motility. The generation of SKOV3GL-G4, a metastatic phenotype of SKOV3 green fluorescent protein and luciferase (GL) ovarian cancer cells, in xenograft murine ascites showed a correlation between metastatic potential and stem cell characteristics, as indicated by the expression of c-Kit, Notch3, Oct4, Nanog and SOX2. Further study revealed that after activation by c-Kit, raft-phospho-PHB Y259 interacted with Notch3 to stabilize Notch3 and increase the downstream target PBX1. Downregulation of raft-phospho-PHB Y259 increased the protein degradation of Notch3 through a lysosomal pathway and inhibited the β-catenin-ABCG2 signaling pathway. Moreover, raft-phospho-PHB Y259 played an important role in ovarian cancer stemness and tumorigenicity as well as resistance to platinum drug treatment in vitro and in vivo.Conclusions: These findings thus reveal a hitherto unreported interrelationship between c-Kit and PHB as well as the effects of raft-phospho-PHB Y259 on ovarian cancer stemness and tumorigenicity mediated by the Notch3 and β-catenin signaling pathways. Targeting the c-Kit/raft-phospho-PHB Y259 axis may provide a new therapeutic strategy for treating patients with ovarian cancer.

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“…Aberrant activation of the Notch signalling pathway has been implicated in numerous human malignancies, including EOC [ [44] , [45] , [46] , [47] ]. Particularly, the amplification of the chr19p13.12 region ( Notch3 ) and its up-regulation at mRNA and protein levels have been detected in a large percentage of OC [ 48 , 49 ]. Another example of alteration in this pathway is the CXCR4/SDF1α chemokine system, which plays a key role in EOC cell biology [ 50 ].…”

Section: Proliferation and Cell Growthmentioning

confidence: 99%

The hallmarks of ovarian cancer: proliferation and cell growth

López-Reig

Löpez‐Guerrero

2020

European Journal of Cancer Supplements

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Epithelial ovarian cancer (EOC) is a heterogeneous group of diseases with distinct biological and clinical behaviour. Despite the differences between them, the capability of tumour cells to continuously proliferate and avoid death is maintained among histotypes. This ability is the result of alterations at different levels, causing the deregulation of cell cycle and proliferative-related pathways. Even if the leading role is played by RB and TP53, changes in other molecular pathways are involved in the development of EOC. This ability can be exploited to generate in vitro and in vivo models resembling the conditions of tumour development in a patient. In vivo models, such as patient-derived xenografts (PDX) or genetically engineered mouse models (GEMM), represent a fundamental tool in the study of the molecular mechanisms implicated in each EOC biotype for testing new therapeutic approaches. Herein we describe the major proliferation-related pathways and its disruption found in EOC and how these features can be used to establish in vivo models for translational research.

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Notch3 Targeting: A Novel Weapon against Ovarian Cancer Stem Cells

Cited by 23 publications

References 70 publications

Therapeutic senescence via GPCR activation in synovial fibroblasts facilitates resolution of arthritis

Therapeutic senescence via GPCR activation in synovial fibroblasts facilitates resolution of arthritis

A novel c-Kit/phospho-prohibitin axis enhances ovarian cancer stemness and chemoresistance via Notch3—PBX1 and β-catenin—ABCG2 signaling

The hallmarks of ovarian cancer: proliferation and cell growth

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