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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.
Cell Death Discov ; 5: 137, 2019.
Article in English | MEDLINE | ID: mdl-31583120

ABSTRACT

Gliomas aberrantly express programmed cell death ligand-1 (PD-L1), which has a pivotal role in immunoevasion. The splicing isoform of FKBP5, termed FKBP51s, is a PD-L1 foldase, assisting the immune checkpoint molecule in maturation and expression on the plasma membrane. The concept that PD-L1 supports tumor-intrinsic properties is increasingly emerging. The aim of the present work was to confirm the pro-tumoral effect of PD-L1 on human glioma cell survival, stemness capacity and resistance, and to address the issue of whether, by targeting its foldase either chemically or by silencing, the aggressive tumor features could be attenuated. PD-L1-depleted glioma cells have a reduced threshold for apoptosis, while PD-L1 forced expression increases resistance. Similar results were obtained with FKBP51s modulation. The ability of PD-L1 to counteract cell death was hampered by FKBP51s silencing. PD-L1 expression was particularly high in glioma cells with a cancer-stem-cell profile. Moreover, PD-L1 sustained the spheroid formation capability of glioma cells. Targeting of FKBP51s by small-interfering RNA (siRNA) or the specific inhibitor SAFit2, reduced the number of formed spheroids, along with PD-L1 expression. Finally, in an orthotopic mouse model of glioblastoma, daily treatment with SAFit2 significantly reduced tumor PD-L1 expression, and tumor growth. In treated mice, caspase-3 activation and reduced vimentin expression were observed in excised tumors. In conclusion, targeting of FKBP51s hampers PD-L1 and its pro-tumoral properties, thereby affecting the self-renewal and growth capacities of glioblastoma cells in vitro and in vivo.

3.
FEBS J ; 286(6): 1120-1135, 2019 03.
Article in English | MEDLINE | ID: mdl-30695232

ABSTRACT

Cell migration is an important process that occurs during development and has also been linked to the motility of cancer cells. Cytoskeleton reorganization takes place in the migration process leading to lamellipodia formation. Understanding the molecular underpinnings of cell migration is particularly important in studies of glioblastoma, a highly invasive and aggressive cancer type. Two members of the phosphoinositide 5-phosphatase family, SKIP and SHIP2, have been associated with cell migration in glioblastoma; however, the precise role these enzymes play in the process-and whether they work in concert-remains unclear. Here, we compared phosphoinositide 5-phosphatases expression in glioblastoma primary cells and cell lines and showed that SHIP2 and SKIP expression greatly varies between different cell types, while OCRL, another phosphoinositide 5-phosphatase, is constitutively expressed. Upon adhesion of U-251 MG cells to fibronectin, SHIP2, SKIP, and PI(4,5)P2 colocalized in membrane ruffles. Upregulation of PI(4,5)P2 was observed in SKIP-depleted U-251 MG cells compared to control cells, but only when cells were adhered to fibronectin. Both PTEN-deficient (U-251) and PTEN-containing (LN229) glioblastoma cells showed a decrease in cell migration velocity in response to SKIP downregulation. Moreover, a SHIP2 catalytic inhibitor lowered cell migration velocity in the U-251 MG cell line. We conclude that integrin activation in U-251 cells leads to colocalization of both SKIP and SHIP2 in ruffles, where they act as potential drivers of cell migration. Depending on their expression levels in glioblastoma, phosphoinositide 5-phosphatases could cooperate and synergize in the regulation of cell migration and adhesion.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Cell Movement , Fibronectins/metabolism , Glioblastoma/pathology , Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases/metabolism , Phosphoric Monoester Hydrolases/metabolism , Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Adaptor Proteins, Signal Transducing/genetics , Glioblastoma/genetics , Glioblastoma/metabolism , Humans , Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases/genetics , RNA, Small Interfering/genetics , Signal Transduction , Tumor Cells, Cultured
4.
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
5.
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.

6.
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
7.
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
8.
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
9.
Neuro Oncol ; 17(1): 81-94, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25085362

ABSTRACT

BACKGROUND: Patients with glioblastoma multiforme (GBM) have an overall median survival of 15 months. This catastrophic survival rate is the consequence of systematic relapses that could arise from remaining glioblastoma stem cells (GSCs) left behind after surgery. We previously demonstrated that GSCs are able to escape the tumor mass and specifically colonize the adult subventricular zones (SVZs) after transplantation. This specific localization, away from the initial injection site, therefore represents a high-quality model of a clinical obstacle to therapy and relapses because GSCs notably retain the ability to form secondary tumors. METHOD: In this work, we questioned the role of the CXCL12/CXCR4 signaling in the GSC-specific invasion of the SVZs. RESULTS: We demonstrated that both receptor and ligand are respectively expressed by different GBM cell populations and by the SVZ itself. In vitro migration bio-assays highlighted that human U87MG GSCs isolated from the SVZs (U87MG-SVZ) display stronger migratory abilities in response to recombinant CXCL12 and/or SVZ-conditioned medium (SVZ-CM) compared with cancer cells isolated from the tumor mass (U87MG-TM). Moreover, in vitro inhibition of the CXCR4 signaling significantly decreased the U87MG-SVZ cell migration in response to the SVZ-CM. Very interestingly, treating U87MG-xenografted mice with daily doses of AMD3100, a specific CXCR4 antagonist, prevented the specific invasion of the SVZ. Another in vivo experiment, using CXCR4-invalidated GBM cells, displayed similar results. CONCLUSION: Taken together, these data demonstrate the significant role of the CXCL12/CXCR4 signaling in this original model of brain cancer invasion.


Subject(s)
Brain Neoplasms/metabolism , Chemokine CXCL12/metabolism , Glioblastoma/metabolism , Lateral Ventricles/metabolism , Neoplasm Invasiveness/physiopathology , Neoplastic Stem Cells/metabolism , Receptors, CXCR4/metabolism , Animals , Benzylamines , Brain Neoplasms/pathology , Cell Line, Tumor , Cyclams , Disease Models, Animal , Female , Glioblastoma/pathology , Heterocyclic Compounds/pharmacology , Humans , Lateral Ventricles/drug effects , Lateral Ventricles/pathology , Mice , Mice, Nude , Receptors, CXCR4/antagonists & inhibitors , Signal Transduction
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