scholarly journals Suppression of Ribosome Biogenesis by Targeting WD Repeat Domain 12 (WDR12) Inhibits Glioma Stem-Like Cell Growth

2021 ◽  
Vol 11 ◽  
Author(s):  
Lanjuan Mi ◽  
Qinghui Qi ◽  
Haowen Ran ◽  
Lishu Chen ◽  
Da Li ◽  
...  
Keyword(s):  
Cell Growth ◽  
Tumor Cells ◽  
Ribosome Biogenesis ◽  
Primary Brain Tumor ◽  
Normal Brain ◽  
28S Rrna ◽  
Malignant Growth ◽  
Animal Survival ◽  
Repeat Domain ◽  
Wd Repeat

Glioma stem-like cells (GSCs) are a subset of tumor cells that initiate malignant growth and promote the therapeutic resistance of glioblastoma, the most lethal primary brain tumor. Ribosome biogenesis is an essential cellular process to maintain cell growth, but its regulatory mechanism in GSCs remains largely unknown. Here, we show that WD repeat domain 12 (WDR12), a component of the Pes1-Bop1 complex (PeBoW), is required for ribosome biogenesis in GSCs. WDR12 is preferentially expressed in GSCs compared to non-stem tumor cells and normal brain cells. High levels of WDR12 are associated with glioblastoma progression and poor prognosis. Silencing WDR12 results in the degradation of PeBoW complex components and prevents the maturation of 28S rRNA, thereby inhibiting ribosome biogenesis in GSCs. Subsequently, WDR12 depletion compromises GSC proliferation, inhibits GSC-derived orthotopic tumor growth, and extends animal survival. Together, our results suggest that WDR12 is crucial for ribosome biogenesis in GSCs, and is thus a potential target for GSC-directed therapy of glioblastoma.

scholarly journals Las1L Is a Nucleolar Protein Required for Cell Proliferation and Ribosome Biogenesis

2010 ◽  
Vol 30 (18) ◽  
pp. 4404-4414 ◽  
Author(s):  
Christopher D. Castle ◽  
Erica K. Cassimere ◽  
Jinho Lee ◽  
Catherine Denicourt
Keyword(s):  
Cell Proliferation ◽  
Cell Growth ◽  
Ribosome Biogenesis ◽  
Ribosomal Subunit ◽  
Nucleolar Protein ◽  
28S Rrna ◽  
Rrna Processing ◽  
Tumor Suppressor P53 ◽  
Growth Increase ◽  
Multistep Process

ABSTRACT Ribosome biogenesis is a highly regulated process ensuring that cell growth (increase in biomass) is coordinated with cell proliferation. The formation of eukaryotic ribosomes is a multistep process initiated by the transcription and processing of rRNA in the nucleolus. Concomitant with this, several preribosomal particles, which transiently associate with numerous nonribosomal factors before mature 60S and 40S subunits are formed and exported in the cytoplasm, are generated. Here we identify Las1L as a previously uncharacterized nucleolar protein required for ribosome biogenesis. Depletion of Las1L causes inhibition of cell proliferation characterized by a G1 arrest dependent on the tumor suppressor p53. Moreover, we demonstrate that Las1L is crucial for ribosome biogenesis and that depletion of Las1L leads to inhibition of rRNA processing and failure to synthesize the mature 28S rRNA. Taken together, our data demonstrate that Las1L is essential for cell proliferation and biogenesis of the 60S ribosomal subunit.

scholarly journals WD Repeat Domain 77 Protein Regulates Translation of E2F1 and E2F3 mRNA

2020 ◽  
Vol 40 (24) ◽  
Author(s):  
Mahmood Anber Altayyar ◽  
Xiumei Sheng ◽  
Zhengxin Wang
Keyword(s):  
Cell Growth ◽  
Translational Regulation ◽  
Cellular Proliferation ◽  
Inhibitory Effect ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Lung Tumorigenesis ◽  
Prostate Tumorigenesis ◽  
Repeat Domain ◽  
Wd Repeat

ABSTRACT WD repeat domain 77 protein (WDR77) is required for cellular proliferation of lung and prostate epithelial cells during earlier stages of development and is reactivated during prostate and lung tumorigenesis. WDR77 plays an essential role in prostate tumorigenesis and cell growth mediated by growth regulatory factors. Here, we identified E2F1 and E2F3 mRNAs as translational targets of WDR77. We demonstrated that WDR77 regulated the translation of E2F1 and E2F3 mRNAs through the 5′ untranslated regions (UTRs) of E2F1 and E2F3 (E2F1/3) mRNAs. WDR77 physically interacted with programmed cell death 4 (PDCD4) that suppresses translation of mRNAs containing structured 5′ UTRs by interacting with eukaryotic translation initiation factor 4A (eIF4A) and inhibiting its helicase activity. Further, we demonstrated that the interaction between WDR77 and PDCD4 prevented the binding of PDCD4 to eIF4A and relieved PDCD4's inhibitory effect on eIF4A1. Overall, our work reveals for the first time that WDR77 is directly involved in translational regulation of E2F1/3 mRNAs through their structured 5′ UTRs, PDCD4, and eIF4A1 and provides novel insight into the cell growth controlled by WDR77.

scholarly journals Macrophages and microglia: the cerberus of glioblastoma

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Alice Buonfiglioli ◽  
Dolores Hambardzumyan
Keyword(s):  
Tumor Cells ◽  
Innate Immune System ◽  
Tumor Heterogeneity ◽  
Expression Profiles ◽  
Brain Parenchyma ◽  
Innate Immune ◽  
Malignant Growth ◽  
Neoplastic Cells ◽  
Functional Roles ◽  
The Brain

AbstractGlioblastoma (GBM) is the most aggressive and deadliest of the primary brain tumors, characterized by malignant growth, invasion into the brain parenchyma, and resistance to therapy. GBM is a heterogeneous disease characterized by high degrees of both inter- and intra-tumor heterogeneity. Another layer of complexity arises from the unique brain microenvironment in which GBM develops and grows. The GBM microenvironment consists of neoplastic and non-neoplastic cells. The most abundant non-neoplastic cells are those of the innate immune system, called tumor-associated macrophages (TAMs). TAMs constitute up to 40% of the tumor mass and consist of both brain-resident microglia and bone marrow-derived myeloid cells from the periphery. Although genetically stable, TAMs can change their expression profiles based upon the signals that they receive from tumor cells; therefore, heterogeneity in GBM creates heterogeneity in TAMs. By interacting with tumor cells and with the other non-neoplastic cells in the tumor microenvironment, TAMs promote tumor progression. Here, we review the origin, heterogeneity, and functional roles of TAMs. In addition, we discuss the prospects of therapeutically targeting TAMs alone or in combination with standard or newly-emerging GBM targeting therapies.

scholarly journals Dual Specificity Kinase DYRK3 Promotes Aggressiveness of Glioblastoma by Altering Mitochondrial Morphology and Function

2021 ◽  
Vol 22 (6) ◽  
pp. 2982
Author(s):  
Kyeongmin Kim ◽  
Sungmin Lee ◽  
Hyunkoo Kang ◽  
Eunguk Shin ◽  
Hae Yu Kim ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Metabolic Flux ◽  
Mitochondrial Fission ◽  
Mammalian Target Of Rapamycin ◽  
Primary Brain Tumor ◽  
Metabolic Reprogramming ◽  
Migration And Invasion ◽  
Mitochondrial Morphology ◽  
Dual Specificity ◽  
Novel Strategy

Glioblastoma multiforme (GBM) is a malignant primary brain tumor with poor patient prognosis. Although the standard treatment of GBM is surgery followed by chemotherapy and radiotherapy, often a small portion of surviving tumor cells acquire therapeutic resistance and become more aggressive. Recently, altered kinase expression and activity have been shown to determine metabolic flux in tumor cells and metabolic reprogramming has emerged as a tumor progression regulatory mechanism. Here we investigated novel kinase-mediated metabolic alterations that lead to acquired GBM radioresistance and malignancy. We utilized transcriptomic analyses within a radioresistant GBM orthotopic xenograft mouse model that overexpresses the dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3). We find that within GBM cells, radiation exposure induces DYRK3 expression and DYRK3 regulates mammalian target of rapamycin complex 1 (mTORC1) activity through phosphorylation of proline-rich AKT1 substrate 1 (PRAS40). We also find that DYRK3 knockdown inhibits dynamin-related protein 1 (DRP1)-mediated mitochondrial fission, leading to increased oxidative phosphorylation (OXPHOS) and reduced glycolysis. Importantly, enforced DYRK3 downregulation following irradiation significantly impaired GBM cell migration and invasion. Collectively, we suggest DYRK3 suppression may be a novel strategy for preventing GBM malignancy through regulating mitochondrial metabolism.

scholarly journals CBIO-11. NOVEL THERAPY TO TARGET PR-RECURRENT GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii17-ii18
Author(s):  
Masum Rahman ◽  
Ian E Olson ◽  
Rehan Saber ◽  
Jibo Zhang ◽  
Lucas P Carlstrom ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Tumor Recurrence ◽  
Primary Brain Tumor ◽  
Differential Sensitivity ◽  
Proliferating Cells ◽  
Novel Therapy ◽  
Conventional Radiation ◽  
Long Time ◽  
Radiation Induced

Abstract BACKGROUND Glioblastoma is a fatal infiltrative primary brain tumor, and standard care includes maximal safe surgical resection followed by radiation and Temozolomide (TMZ). Therapy-resistant residual cells persist in a latent state a long time before inevitable recurrence. Conventional radiation and Temozolomide (TMZ) treatment cause oxidative stress and DNA damage resulting senescent-like state of cell-cycle arrest. However, increasing evidence demonstrates escaping senescence leads to tumor recurrence. Thus, the ablation of senescent tumor cells after chemoradiation may be an avenue to limit tumor recurrence. METHODS 100uM TMZ for 7days or 10-20Gy radiation (cesium gamma radiator) was used for senescence induction in human glioblastoma in vitro and confirmed by SA-Beta gal staining and PCR. Replication arrest assessed by automated quantification of cellular confluence (Thermo Scientific Series 8000 WJ Incubator). We evaluated the IC50 for several senolytics targeting multiple SCAPs, including Dasatinib, Quercetin, AMG-232, Fisetin, Onalespib, Navitoclax, and A1331852, and in senescent vs. proliferating cells. RESULTS Among the senolytic tested, the Bcl-XL inhibitors A1331852 and Navitoclax both shown senolytic effect by selectively killing radiated, senescent tumor cells at lower concentrations as compared to 0Gy treated non-senescent cells. Across 12 GBM cell lines, IC50 for senescent cells was 6–500 times lower than non-senescent GBM(p< 0.005). Such differential sensitivity to Bcl-XL inhibition after radiation has also observed by BCL-XL knockdown in radiated glioma. CONCLUSION These findings suggest the potential to harness radiation-induced biology to ablate surviving quiescent cells and demonstrate Bcl-XL dependency as a potential vulnerability of surviving tumor cells after exposure to chemoradiation.

scholarly journals EXTH-70. ENHANCEMENT OF ANTITUMOR ACTIVITY BY USING 5-ALA–MEDIATED SONODYNAMIC THERAPY TO INDUCE APOPTOSIS AND NECROSIS IN A MOUSE GLIOMA MODEL

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi97-vi97
Author(s):  
Satoshi Suehiro ◽  
Takanori Ohnishi ◽  
Akihiro Inoue ◽  
Daisuke Yamashita ◽  
Masahiro Nishikawa ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Malignant Gliomas ◽  
Glioma Cells ◽  
High Intensity Focused Ultrasound ◽  
Control Group ◽  
Normal Brain ◽  
Sonodynamic Therapy ◽  
Cytotoxic Effects

Abstract OBJECTIVE High invasiveness of malignant gliomas frequently causes local tumor recurrence. To control such recurrence, novel therapies targeted toward infiltrating glioma cells are required. Here, we examined cytotoxic effects of sonodynamic therapy (SDT) combined with a sonosensitizer, 5-aminolevulinic acid (5-ALA), on malignant gliomas both in vitro and in vivo. METHODS In vitro cytotoxicity of 5-ALA-SDT was evaluated in U87 and U251 glioma cells and in U251Oct-3/4 glioma stemlike cells. Treatment-related apoptosis was analyzed using flow cytometry. Intracellular reactive oxygen species (ROS) were measured and the role of ROS in treatment-related cytotoxicity was examined. Effects of 5-ALA-SDT with high-intensity focused ultrasound (HIFU) on tumor growth, survival of glioma-transplanted mice, and histological features of the mouse brains were investigated. RESULTS The 5-ALA-SDT inhibited cell growth and changed cell morphology. Flow cytometric analysis indicated that 5-ALA-SDT induced apoptotic cell death. The 5-ALA-SDT generated higher ROS than in the control group, and inhibition of ROS generation completely eliminated the cytotoxic effects of 5-ALA-SDT. In the in vivo study, 5-ALA-SDT with HIFU greatly prolonged survival of the tumor-bearing mice compared with that of the control group (p < 0.05). Histologically, 5-ALA-SDT produced mainly necrosis of the tumor tissue in the focus area and induced apoptosis of the tumor cells in the perifocus area around the target of the HIFU-irradiated field. Normal brain tissues around the ultrasonic irradiation field of HIFU remained intact. CONCLUSIONS The 5-ALA-SDT was cytotoxic toward malignant gliomas. Generation of ROS by the SDT was thought to promote apoptosis of glioma cells. The 5-ALA-SDT with HIFU induced tumor necrosis in the focus area and apoptosis in the perifocus area of the HIFU-irradiated field. These results suggest that 5-ALA-SDT with HIFU may present a less invasive and tumor-specific therapy, not only for a tumor mass but also for infiltrating tumor cells in malignant gliomas.

JHDM1B expression regulates ribosome biogenesis and cancer cell growth in a p53 dependent manner

2014 ◽  
Vol 136 (5) ◽  
pp. E272-E281 ◽  
Author(s):  
Marianna Penzo ◽  
Lucia Casoli ◽  
Daniela Pollutri ◽  
Laura Sicuro ◽  
Claudio Ceccarelli ◽  
...  
Keyword(s):  
Cell Growth ◽  
Cancer Cell ◽  
Ribosome Biogenesis ◽  
Dependent Manner ◽  
Cancer Cell Growth

Production of matrix metalloproteinases and tissue inhibitor of metalloproteinases-1 by human brain tumors

1994 ◽  
Vol 81 (1) ◽  
pp. 69-77 ◽  
Author(s):  
Takao Nakagawa ◽  
Toshihiko Kubota ◽  
Masanori Kabuto ◽  
Kazufumi Sato ◽  
Hirokazu Kawano ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Matrix Metalloproteinases ◽  
Brain Tumors ◽  
Human Brain ◽  
Tumor Cells ◽  
Tumor Invasion ◽  
Gelatinolytic Activity ◽  
Normal Brain ◽  
Tissue Inhibitor Of Metalloproteinases ◽  
Human Brain Tumor

✓ The role of matrix metalloproteinases (MMP's) and their inhibitor, tissue inhibitor of metalloproteinases-1 (TIMP-1), in human brain tumor invasion was investigated. Gelatinolytic activity was assayed via gelatin zymography, and four MMP's (MMP-1, MMP-2, MMP-3, and MMP-9) and TIMP-1 were immunolocalized in human brain tumors and in normal brain tissues using monoclonal antibodies. The tissue was surgically removed from 44 patients: glioblastoma (five cases), anaplastic astrocytoma (six cases), astrocytoma (four cases), metastatic tumor (six cases), neurinoma (10 cases), meningioma (10 cases), and normal brain tissue (three cases). Glioblastomas, anaplastic astrocytomas, and metastatic tumors showed high gelatinolytic activity and positive immunostaining for MMP's; TIMP-1 was also expressed in these tumors, but some tumor cells were negative for the antibody. Astrocytomas had low gelatinolytic activity and the tumor cells showed no immunoreactivity for MMP's and TIMP-1. Although neurinomas and meningiomas had only moderate proteinase activity and exhibited positive immunoreactivity for MMP-9, intense expression of TIMP-1 was simultaneously observed in these tumor cells. These findings suggest that MMP's play an important role in human brain tumor invasion, probably due to an imbalance between the production of MMP's and TIMP-1 by the tumor cells.

The deposition of Hg203-chlormerodrin in experimental brain tumors

1971 ◽  
Vol 35 (3) ◽  
pp. 303-308 ◽  
Author(s):  
Tatsuya Kobayashi ◽  
Louis Bakay ◽  
Joseph C. Lee
Keyword(s):  
Brain Tumors ◽  
Tumor Cells ◽  
Normal Brain ◽  
Intracranial Tumors ◽  
Electron Microscopic ◽  
Electron Microscopic Autoradiography ◽  
Content Type ◽  
Meningeal Tumors ◽  
Vacuolar System ◽  
Fine Print

✓ The deposition of Hg203-chlormerodrin was studied in intracranial tumors in mice induced by implantation of 20-methyl cholanthrene by tissue assay, as well as light microscopic and electron microscopic autoradiography. The investigations were carried out in astrocytomas, glioblastomas, and meningeal tumors. The chlormerodrin content of the tumors exceeded that of normal brain with a significant tumor/brain ratio ranging from 5.8 to 22.5. It was found that the chlormerodrin molecule becomes rapidly incorporated in the tumor cells, with a preference for that portion of the cytoplasm associated with the vacuolar system.

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