261 research outputs found
Effect of Argania spinosa oil extract on proliferation and Notch1 and ERK1/2 signaling of T-cell acute lymphoblastic leukemia cell lines
The Argan tree, called Argania spinosa (L.) Skeels, is a tropical plant, which belongs to the Sapotaceae family, it is exploited essentially for its fruits. The endosperm seed of the fruit constitutes a good potential source of edible oil for human consumption and is endowed with important medicinal properties such as antioxidant, antimalarial and anti-proliferative. The aim of the present work is to evaluate the anti-proliferative effect of the oil extracted from seeds of A. spinosa in T-cell acute lymphoblastic leukemia human (T-ALL) context. The activity was assessed through an in vitro test on three T-ALL cell lines: JURKAT, MOLT3 and DND41. The cytotoxicity effects of A. spinosa oil extract were checked by MTT assay and the change in the activity levels of two T-ALL proliferation-related proteins (Notch1 and ERK) was investigated by Western blot, the results demonstrate that treatment with A. spinosa oil extract at the dose of 100 μg/mL inhibited the growth of JURKAT, MOLT3 and DND41 cells, and reduced the expression levels and the activity of proliferation-related proteins such as ERK1/2 and Notch1 intracellular domain. A. spinosa oil extract could be a potential preventive and therapeutic approach recommended as anti-proliferative against leukemia
Wnt, notch, and TGF-β pathways impinge on hedgehog signaling complexity: an open window on cancer
Constitutive activation of the Hedgehog (Hh) signaling pathway is associated with increased risk of developing several malignancies. The biological and pathogenic importance of Hh signaling emphasizes the need to control its action tightly, both physiologically and therapeutically. Evidence of crosstalk between Hh and other signaling pathways is reported in many tumor types. Here, we provide an overview of the current knowledge about the communication between Hh and major signaling pathways, such as Notch, Wnt, and transforming growth factor beta (TGF-beta), which play critical roles in both embryonic and adult life. When these pathways are unbalanced, impaired crosstalk contributes to disease development. It is reported that more than one of these pathways are active in different type of tumors, at the same time. Therefore, starting from a plethora of stimuli that activate multiple signaling pathways, we describe the signals that preferentially converge on the Hh signaling cascade that influence its activity. Moreover, we highlight several connection points between Hh and Notch, Wnt, or TGF-beta pathways, showing a reciprocal synergism that contributes to tumorigenesis, supporting a more malignant behavior by tumor cells, such as in leukemia and brain tumors. Understanding the importance of these molecular interlinking networks will provide a rational basis for combined anticancer drug development
Notch3 targeting. A novel weapon against ovarian cancer stem cells
Notch signaling is frequently activated in ovarian cancer (OC) and contributes to the proliferation and survival of cultured OC cells as well as to tumor formation and angiogenesis in xenograft models. Several studies demonstrate that Notch3 expression renders cancer cells more resistant to carboplatin, contributing to chemoresistance and poor survival of OC-bearing patients. This suggests that Notch3 can represent both a biomarker and a target for therapeutic interventions in OC patients. Although it is still unclear how chemoresistance arises, different lines of evidence support a critical role of cancer stem cells (CSCs), suggesting that CSC targeting by innovative therapeutic approaches might represent a promising tool to efficiently reduce OC recurrence. To date, CSC-directed therapies in OC tumors are mainly targeted to the inhibition of CSC-related signaling pathways, including Notch. As it is increasingly evident the involvement of Notch signaling, and in particular of Notch3, in regulating stem-like cell maintenance and expansion in several tumors, here we provide an overview of the current knowledge of Notch3 role in CSC-mediated OC chemoresistance, finally exploring the potential design of innovative Notch3 inhibition-based therapies for OC treatment, aimed at eradicating tumor through the suppression of CSCs
Notch and NF-kB: Coach and Players of Regulatory T-Cell Resposnse in Cancer
The Notch signaling pathway plays multiple roles in driving T-cell fate decisions,
proliferation, and aberrant growth. NF-kB is a cell-context key player interconnected
with Notch signaling either in physiological or in pathological conditions. This review
focuses on how themultilayered crosstalk between different Notches and NF-kB subunits
may converge on Foxp3 gene regulation and orchestrate CD4+ regulatory T (Treg)
cell function, particularly in a tumor microenvironment. Notably, Treg cells may play a
pivotal role in the inhibition of antitumor immune responses, possibly promoting tumor
growth. A future challenge is represented by further dissection of both Notch and NF-kB
pathways and consequences of their intersection in tumor-associated Treg biology. This
may shed light on themolecularmechanisms regulating Treg cell expansion andmigration
to peripheral lymphoid organs thought to facilitate tumor development and still to be
explored. In so doing, new opportunities for combined and/or more selective therapeutic
Q25 approaches to improve anticancer immunity may be found
The epigenetic factor BORIS/CTCFL regulates the NOTCH3 gene expression in cancer cells.
Aberrant upregulation of NOTCH3 gene plays a critical role in cancer pathogenesis. However, the underlying mechanisms are still unknown. We tested here the hypothesis that aberrant epigenetic modifications in the NOTCH3 promoter region might account for its upregulation in cancer cells. We compared DNA and histone methylation status of NOTCH3 promoter region in human normal blood cells and T cell acute lymphoblastic leukemia (T-ALL) cell lines, differentially expressing NOTCH3. We found that histone methylation, rather than DNA hypomethylation, contributes towards establishing an active chromatin status of NOTCH3 promoter in NOTCH3 overexpressing cancer cells. We discovered that the chromatin regulator protein BORIS/CTCFL plays an important role in regulating NOTCH3 gene expression. We observed that BORIS is present in T-ALL cell lines as well as in cell lines derived from several solid tumors overexpressing NOTCH3. Moreover, BORIS targets NOTCH3 promoter in cancer cells and it is able to induce and to maintain a permissive/active chromatin conformation. Importantly, the association between NOTCH3 overexpression and BORIS presence was confirmed in primary T-ALL samples from patients at the onset of the disease. Overall, our results provide novel insights into the determinants of NOTCH3 overexpression in cancer cells, by revealing a key role for BORIS as the main mediator of transcriptional deregulation of NOTCH3. Copyright © 2014 Elsevier B.V. All rights reserved
The epigenetic factor BORIS/CTCFL regulates the NOTCH3 gene expression in cancer cells.
International audience; Aberrant upregulation of NOTCH3 gene plays a critical role in cancer pathogenesis. However, the underlying mechanisms are still unknown. We tested here the hypothesis that aberrant epigenetic modifications in the NOTCH3 promoter region might account for its upregulation in cancer cells. We compared DNA and histone methylation status of NOTCH3 promoter region in human normal blood cells and T cell acute lymphoblastic leukemia (T-ALL) cell lines, differentially expressing NOTCH3. We found that histone methylation, rather than DNA hypomethylation, contributes towards establishing an active chromatin status of NOTCH3 promoter in NOTCH3 overexpressing cancer cells. We discovered that the chromatin regulator protein BORIS/CTCFL plays an important role in regulating NOTCH3 gene expression. We observed that BORIS is present in T-ALL cell lines as well as in cell lines derived from several solid tumors overexpressing NOTCH3. Moreover, BORIS targets NOTCH3 promoter in cancer cells and it is able to induce and to maintain a permissive/active chromatin conformation. Importantly, the association between NOTCH3 overexpression and BORIS presence was confirmed in primary T-ALL samples from patients at the onset of the disease. Overall, our results provide novel insights into the determinants of NOTCH3 overexpression in cancer cells, by revealing a key role for BORIS as the main mediator of transcriptional deregulation of NOTCH3
Notch signaling sustains the expression of Mcl-1 and the activity of eIF4E to promote cell survival in CLL
In chronic lymphocytic leukemia (CLL), Notch1 and Notch2 signaling is constitutively activated and contributes to apoptosis resistance. We show that genetic inhibition of either Notch1 or Notch2, through small-interfering RNA, increases apoptosis of CLL cells and is associated with decreased levels of the anti-apoptotic protein Mcl-1. Thus, Notch signaling promotes CLL cell survival at least in part by sustaining Mcl-1 expression. In CLL cells, an enhanced Notch activation also contributes to the increase in Mcl-1 expression and cell survival induced by IL-4.Mcl-1 downregulation by Notch targeting is not due to reduced transcription or degradation by caspases, but in part, to increased degradation by the proteasome. Mcl-1 downregulation by Notch targeting is also accompanied by reduced phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), suggesting that this protein is another target of Notch signaling in CLL cells.Overall, we show that Notch signaling sustains CLL cell survival by promoting Mcl-1 expression and eIF4E activity, and given the oncogenic role of these factors, we underscore the therapeutic potential of Notch inhibition in CLL
Inhibition of Hedgehog-dependent tumors and cancer stem cells by a newly identified naturally occurring chemotype
Hedgehog (Hh) inhibitors have emerged as valid tools in the treatment of a wide range of cancers. Indeed, aberrant activation of the Hh pathway occurring either by ligand-dependent or -independent mechanisms is a key driver in tumorigenesis. The smoothened (Smo) receptor is one of the main upstream transducers of the Hh signaling and is a validated target for the development of anticancer compounds, as underlined by the FDA-approved Smo antagonist Vismodegib (GDC-0449/Erivedge) for the treatment of basal cell carcinoma. However, Smo mutations that confer constitutive activity and drug resistance have emerged during treatment with Vismodegib. For this reason, the development of new effective Hh inhibitors represents a major challenge for cancer therapy. Natural products have always represented a unique source of lead structures in drug discovery, and in recent years have been used to modulate the Hh pathway at multiple levels. Here, starting from an in house library of natural compounds and their derivatives, we discovered novel chemotypes of Hh inhibitors by mean of virtual screening against the crystallographic structure of Smo. Hh functional based assay identified the chalcone derivative 12 as the most effective Hh inhibitor within the test set. The chalcone 12 binds the Smo receptor and promotes the displacement of Bodipy-Cyclopamine in both Smo WT and drug-resistant Smo mutant. Our molecule stands as a promising Smo antagonist able to specifically impair the growth of Hh-dependent tumor cells in vitro and in vivo and medulloblastoma stem-like cells and potentially overcome the associated drug resistance
MicroRNAs-Proteomic Networks Characterizing Human Medulloblastoma-SLCs
Medulloblastoma (MB) is the most common malignant brain tumor of pediatric age and is characterized by cells expressing stem, astroglial, and neuronal markers. Among them, stem-like cells (hMB-SLCs) represent a fraction of the tumor cell population with the potential of self-renewal and proliferation and have been associated with tumor poor prognosis. In this context, microRNAs have been described as playing a pivotal role in stem cells differentiation. In our paper, we analyze microRNAs profile and genes expression of hMB-SLCs before and after Retinoic Acid- (RA-) induced differentiation. We aimed to identify pivotal players of specific pathways sustaining stemness and/or tumor development and progression and integrate the results of our recent proteomic study. Our results uncovered 22 differentially expressed microRNAs that were used as input together with deregulated genes and proteins in the Genomatix Pathway System (GePS) analysis revealing 3 subnetworks that could be interestingly involved in the maintenance of hMB-SLCs proliferation. Taken together, our findings highlight microRNAs, genes, and proteins that are significantly modulated in hMB-SLCs with respect to their RA-differentiated counterparts and could open new perspectives for prognostic and therapeutic intervention on MB
In vitro and in vivo inhibition of breast cancer cell growth by targeting the Hedgehog/GLI pathway with SMO (GDC-0449) or GLI (GANT-61) inhibitors.
Aberrant Hedgehog (Hh)/glioma-associated oncogene (GLI) signaling has
been implicated in cancer progression. Here, we analyzed GLI1, Sonic Hedgehog
(Shh) and NF-κB expression in 51 breast cancer (ductal carcinoma) tissues using
immunohistochemistry. We found a positive correlation between nuclear GLI1
expression and tumor grade in ductal carcinoma cases. Cytoplasmic Shh staining
significantly correlated with a lower tumor grade. Next, the in vitro effects of two
Hh signaling pathway inhibitors on breast cancer cell lines were evaluated using the
Smoothened (SMO) antagonist GDC-0449 and the direct GLI1 inhibitor GANT-61.
GDC-0449 and GANT-61 exhibited the following effects: a) inhibited breast cancer
cell survival; b) induced apoptosis; c) inhibited Hh pathway activity by decreasing
the mRNA expression levels of GLI1 and Ptch and inhibiting the nuclear translocation
of GLI1; d) increased/decreased EGFR and ErbB2 protein expression, reduced p21-
Ras and ERK1/ERK2 MAPK activities and inhibited AKT activation; and e) decreased
the nuclear translocation of NF-κB. However, GANT-61 exerted these effects more
effectively than GDC-0449. The in vivo antitumor activities of GDC-0449 and GANT-
61 were analyzed in BALB/c mice that were subcutaneously inoculated with mouse
breast cancer (TUBO) cells. GDC-0449 and GANT-61 suppressed tumor growth of
TUBO cells in BALB/c mice to different extents. These findings suggest that targeting
the Hh pathway using antagonists that act downstream of SMO is a more efficient
strategy than using antagonists that act upstream of SMO for interrupting Hh signaling
in breast cancer
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