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1.
Carcinogenesis ; 41(4): 417-429, 2020 06 17.
Article in English | MEDLINE | ID: mdl-31504251

ABSTRACT

Glioblastoma (GBM) is the most frequent and aggressive primary tumor in the central nervous system. Previously, the secretion of CXCL12 in the brain subventricular zones has been shown to attract GBM cells and protect against irradiation. However, the exact molecular mechanism behind this radioprotection is still unknown. Here, we demonstrate that CXCL12 modulates the phosphorylation of MAP kinases and their regulator, the nuclear MAP kinase phosphatase 1 (MKP1). We further show that MKP1 is able to decrease GBM cell death and promote DNA repair after irradiation by regulating major apoptotic players, such as Jun-N-terminal kinase, and by stabilizing the DNA repair protein RAD51. Increases in MKP1 levels caused by different corticoid treatments should be reexamined for GBM patients, particularly during their radiotherapy sessions, in order to prevent or to delay the relapses of this tumor.


Subject(s)
Biomarkers, Tumor/metabolism , Brain Neoplasms/genetics , Chemokine CXCL12/metabolism , DNA Repair , DNA/metabolism , Dual Specificity Phosphatase 1/metabolism , Glioblastoma/genetics , Apoptosis , Biomarkers, Tumor/genetics , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Cell Proliferation , Chemokine CXCL12/genetics , DNA/genetics , DNA/radiation effects , Dual Specificity Phosphatase 1/genetics , Gene Expression Regulation, Neoplastic , Glioblastoma/metabolism , Glioblastoma/pathology , Humans , Phosphorylation , Prognosis , Signal Transduction , Survival Rate , Tumor Cells, Cultured
2.
Oncogene ; 38(1): 73-87, 2019 01.
Article in English | MEDLINE | ID: mdl-30082913

ABSTRACT

Primary glioblastoma is the most frequent human brain tumor in adults and is generally fatal due to tumor recurrence. We previously demonstrated that glioblastoma-initiating cells invade the subventricular zones and promote their radio-resistance in response to the local release of the CXCL12 chemokine. In this work, we show that the mitotic Aurora A kinase (AurA) is activated through the CXCL12-CXCR4 pathway in an ERK1/2-dependent manner. Moreover, the CXCL12-ERK1/2 signaling induces the expression of Ajuba, the main cofactor of AurA, which allows the auto-phosphorylation of AurA.We show that AurA contributes to glioblastoma cell survival, radio-resistance, self-renewal, and proliferation regardless of the exogenous stimulation with CXCL12. On the other hand, AurA triggers the CXCL12-mediated migration of glioblastoma cells in vitro as well as the invasion of the subventricular zone in xenograft experiments. Moreover, AurA regulates cytoskeletal proteins (i.e., Actin and Vimentin) and favors the pro-migratory activity of the Rho-GTPase CDC42 in response to CXCL12. Altogether, these results show that AurA, a well-known kinase of the mitotic machinery, may play alternative roles in human glioblastoma according to the CXCL12 concentration.


Subject(s)
Aurora Kinase A/physiology , Brain Neoplasms/enzymology , Chemokine CXCL12/physiology , Glioblastoma/enzymology , Neoplasm Proteins/physiology , Animals , Brain Neoplasms/pathology , Cell Line, Tumor , Cell Movement/drug effects , Cell Survival , Chemokine CXCL12/pharmacology , Enzyme Activation , Glioblastoma/pathology , Heterografts , Humans , LIM Domain Proteins/biosynthesis , LIM Domain Proteins/genetics , Lateral Ventricles/pathology , MAP Kinase Signaling System , Mice , Neoplasm Invasiveness , Phosphorylation , Protein Processing, Post-Translational , Receptors, CXCR4/physiology , Signal Transduction
3.
Cell Div ; 13: 7, 2018.
Article in English | MEDLINE | ID: mdl-30250494

ABSTRACT

Aurora kinases are serine/threonine kinases essential for the onset and progression of mitosis. Aurora members share a similar protein structure and kinase activity, but exhibit distinct cellular and subcellular localization. AurA favors the G2/M transition by promoting centrosome maturation and mitotic spindle assembly. AurB and AurC are chromosome-passenger complex proteins, crucial for chromosome binding to kinetochores and segregation of chromosomes. Cellular distribution of AurB is ubiquitous, while AurC expression is mainly restricted to meiotically-active germ cells. In human tumors, all Aurora kinase members play oncogenic roles related to their mitotic activity and promote cancer cell survival and proliferation. Furthermore, AurA plays tumor-promoting roles unrelated to mitosis, including tumor stemness, epithelial-to-mesenchymal transition and invasion. In this review, we aim to understand the functional interplay of Aurora kinases in various types of human cells, including tumor cells. The understanding of the functional diversity of Aurora kinases could help to evaluate their relevance as potential therapeutic targets in cancer.

4.
Biochem J ; 474(17): 2903-2924, 2017 08 11.
Article in English | MEDLINE | ID: mdl-28801478

ABSTRACT

Phosphatases and cancer have been related for many years now, as these enzymes regulate key cellular functions, including cell survival, migration, differentiation and proliferation. Dysfunctions or mutations affecting these enzymes have been demonstrated to be key factors for oncogenesis. The aim of this review is to shed light on the role of four different phosphatases (PTEN, PP2A, CDC25 and DUSP1) in five different solid tumors (breast cancer, lung cancer, pancreatic cancer, prostate cancer and ovarian cancer), in order to better understand the most frequent and aggressive primary cancer of the central nervous system, glioblastoma.


Subject(s)
Cell Transformation, Neoplastic/metabolism , Central Nervous System Neoplasms/enzymology , Glioblastoma/enzymology , Neoplasm Proteins/metabolism , Phosphoprotein Phosphatases/metabolism , Animals , Cell Transformation, Neoplastic/genetics , Central Nervous System Neoplasms/genetics , Female , Glioblastoma/genetics , Humans , Male , Neoplasm Proteins/genetics , Phosphoprotein Phosphatases/genetics
5.
Neuro Oncol ; 19(1): 66-77, 2017 01.
Article in English | MEDLINE | ID: mdl-27370398

ABSTRACT

BACKGROUND: Patients with glioblastoma (GBM) have an overall median survival of 15 months despite multimodal therapy. These catastrophic survival rates are to be correlated to systematic relapses that might arise from remaining glioblastoma stem cells (GSCs) left behind after surgery. In this line, it has recently been demonstrated that GSCs are able to escape the tumor mass and preferentially colonize the adult subventricular zone (SVZ). At a distance from the initial tumor site, these GSCs might therefore represent a high-quality model of clinical resilience to therapy and cancer relapses as they specifically retain tumor-initiating abilities. METHOD: While relying on recent findings that have validated the existence of GSCs in the human SVZ, we questioned the role of the SVZ niche as a potential GSC reservoir involved in therapeutic failure. RESULTS: Our results demonstrate that (i) GSCs located in the SVZ are specifically resistant to radiation in vivo, (ii) these cells display enhanced mesenchymal roots that are known to be associated with cancer radioresistance, (iii) these mesenchymal traits are specifically upregulated by CXCL12 (stromal cell-derived factor-1) both in vitro and in the SVZ environment, (iv) the amount of SVZ-released CXCL12 mediates GBM resistance to radiation in vitro, and (v) interferes with the CXCL12/CXCR4 signalling system, allowing weakening of the tumor mesenchymal roots and radiosensitizing SVZ-nested GBM cells. CONCLUSION: Together, these data provide evidence on how the adult SVZ environment, through the release of CXCL12, supports GBM therapeutic failure and potential tumor relapse.


Subject(s)
Brain Neoplasms/pathology , Chemokine CXCL12/metabolism , Cranial Irradiation/adverse effects , Glioblastoma/pathology , Lateral Ventricles/pathology , Neoplastic Stem Cells/pathology , Radiation Tolerance , Animals , Brain Neoplasms/metabolism , Brain Neoplasms/radiotherapy , Gamma Rays/adverse effects , Glioblastoma/metabolism , Glioblastoma/radiotherapy , Humans , Lateral Ventricles/metabolism , Lateral Ventricles/radiation effects , Mice , Mice, Nude , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/radiation effects , Signal Transduction/radiation effects , Tumor Cells, Cultured
6.
Target Oncol ; 12(1): 11-18, 2017 02.
Article in English | MEDLINE | ID: mdl-27573024

ABSTRACT

The main obstacle for the cure of glioblastoma (GBM) is systematic tumor recurrence after treatment. More than 90 % of GBM tumors are indeed recurrent within 5 years after diagnosis and treatment. We urgently need new therapies to specifically address these deadly relapses. A major advance in the understanding of GBM recurrence is the identification of GBM-Initiating Cells (GIC), characterized by their abilities for self-renewal, multilineage differentiation, and proliferation. It appears that these features of GIC could be modulated by the mitotic kinase Aurora A (AurA). Indeed, besides its role in mitosis, AurA has recently been identified to regulate alternative functions like cell polarity, asymmetric cell division, and epithelial to mesenchymal transition. All these properties may help explain GBM therapeutic resistance and recurrence. In this review, we make the hypothesis that AurA could significantly contribute to GBM recurrences and we focus on the possible roles of AurA in GIC.


Subject(s)
Brain Neoplasms/metabolism , Glioblastoma/metabolism , Aurora Kinase A/chemistry , Brain Neoplasms/pathology , Glioblastoma/pathology , Humans
7.
Oncotarget ; 7(51): 84924-84937, 2016 Dec 20.
Article in English | MEDLINE | ID: mdl-27793049

ABSTRACT

Cutaneous squamous cell carcinoma (cSCC) is the most common type of non-melanoma skin cancer that can metastasize. The major etiological factor associated with cSCC is Ultraviolet radiation (UVR) with a limited understanding of its molecular mechanism. It was hypothesized that there is a direct effect of UVR on modulation of microRNAs (miRNAs), a novel class of short noncoding RNAs which affects translation and stability of mRNAs. To test the hypothesis, the dorsal skin of the SKH1 mice (6-7 week old) was exposed to acute and chronic doses of UVR. In miRNA array profiling, we found differential expression (log fold change>1) of miR-25-5p between untreated and acute UVR treated (4kJ/m2) SKH1 mice skin. However, differential expression (>1 log fold) of miR-144-3p, miR-33-5p, miR-32-5p, miR-1983, miR-136-5p, miR-142-3p, miR-376a-3p, miR-142-5p, miR-3968, and miR-29b-3p was observed between untreated and chronically UVR treated mice skin. Differentially expressed selected miRNAs (miR-32-5p, miR-33-5p, miR-144-3p, and miR-376a-3p) were further validated in real time PCR using miRNA specific primers. Web based data mining, for the prediction of potential miRNA associated gene pathways in miRBase database revealed a link with important pathways (PI3K-Akt, MAPK, Wnt, transcriptional misregulation, and other oncogenic pathway) associated with cSCC. Furthermore, findings of PI3K-Akt pathway genes affected due to chronic UVR were confirmed using cDNA array.


Subject(s)
Carcinoma, Squamous Cell/genetics , Dermatology , MicroRNAs/genetics , Skin Neoplasms/genetics , Ultraviolet Rays , Animals , Cells, Cultured , Disease Models, Animal , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Gene Expression Profiling , Gene Expression Regulation/drug effects , Humans , Mice , Mice, Hairless , MicroRNAs/radiation effects , Organ Culture Techniques , Phosphatidylinositol 3-Kinases/metabolism , Research Design , Signal Transduction/genetics , Ultraviolet Rays/adverse effects , Wnt Proteins/metabolism
8.
Oncotarget ; 7(14): 17945-56, 2016 Apr 05.
Article in English | MEDLINE | ID: mdl-26918454

ABSTRACT

Chronic exposure to ultraviolet radiation (UVR) is linked to the development of cutaneous squamous cell carcinoma (SCC), a non-melanoma form of skin cancer that can metastasize. Tumor necrosis factor-alpha (TNFα), a pro-inflammatory cytokine, is linked to UVR-induced development of SCC. To find clues about the mechanisms by which TNFα may promote UVR-induced development of SCC, we investigated changes in the expression profiling of microRNAs (miRNA), a novel class of short noncoding RNAs, which affects translation and stability of mRNAs. In this experiment, TNFα knockout (TNFα KO) mice and their wild type (WT) littermates were exposed to acute UVR (2.0 kJ/m2) and the expression profiling of epidermal miRNA was determined 4hr post UVR exposure. TNFα deletion in untreated WT mice resulted in differential expression (log fold change>1) of seventeen miRNA. UVR exposure in WT mice induced differential expression of 22 miRNA. However, UVR exposure in TNFα KO mice altered only two miRNAs. Four miRNA, were differentially expressed between WT+UVR and TNFα KO+UVR groups. Differentially expressed selected miRNAs were further validated using real time PCR. Few of the differentially expressed miRNAs (miR-31-5p, miR-196a-5p, miR-127-3p, miR-206-3p, miR-411-5p, miR-709, and miR-322-5p) were also observed in UVR-induced SCC. Finally, bio-informatics analysis using DIANA, MIRANDA, Target Scan, and miRDB algorithms revealed a link with major UVR-induced pathways (MAPK, PI3K-Akt, transcriptional mis-regulation, Wnt, and TGF-beta).


Subject(s)
Carcinoma, Squamous Cell/etiology , Epidermis/metabolism , MicroRNAs/biosynthesis , Radiation Injuries, Experimental/etiology , Radiation Injuries, Experimental/metabolism , Skin Neoplasms/etiology , Tumor Necrosis Factor-alpha/biosynthesis , Ultraviolet Rays/adverse effects , Animals , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/metabolism , Epidermis/radiation effects , Mice , Mice, Knockout , MicroRNAs/genetics , Radiation Injuries, Experimental/genetics , Skin Neoplasms/genetics , Skin Neoplasms/metabolism
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