scholarly journals MDA-9/Syntenin regulates protective autophagy in anoikis-resistant glioma stem cells

2018 ◽  
Vol 115 (22) ◽  
pp. 5768-5773 ◽  
Author(s):  
Sarmistha Talukdar ◽  
Anjan K. Pradhan ◽  
Praveen Bhoopathi ◽  
Xue-Ning Shen ◽  
Laura A. August ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Therapy Resistance ◽  
Protective Mechanism ◽  
Glioma Stem Cells ◽  
Loss Of Function ◽  
Egfr Signaling ◽  
Anoikis Resistance ◽  
Functional Link ◽  
Small Subpopulation

Glioma stem cells (GSCs) comprise a small subpopulation of glioblastoma multiforme cells that contribute to therapy resistance, poor prognosis, and tumor recurrence. Protective autophagy promotes resistance of GSCs to anoikis, a form of programmed cell death occurring when anchorage-dependent cells detach from the extracellular matrix. In nonadherent conditions, GSCs display protective autophagy and anoikis-resistance, which correlates with expression of melanoma differentiation associated gene-9/Syntenin (MDA-9) (syndecan binding protein; SDCBP). When MDA-9 is suppressed, GSCs undergo autophagic death supporting the hypothesis that MDA-9 regulates protective autophagy in GSCs under anoikis conditions. MDA-9 maintains protective autophagy through phosphorylation of BCL2 and by suppressing high levels of autophagy through EGFR signaling. MDA-9 promotes these changes by modifying FAK and PKC signaling. Gain-of-function and loss-of-function genetic approaches demonstrate that MDA-9 regulates pEGFR and pBCL2 expression through FAK and pPKC. EGFR signaling inhibits autophagy markers (ATG5, Lamp1, LC3B), helping to maintain protective autophagy, and along with pBCL2 maintain survival of GSCs. In the absence of MDA-9, this protective mechanism is deregulated; EGFR no longer maintains protective autophagy, leading to highly elevated and sustained levels of autophagy and consequently decreased cell survival. In addition, pBCL2 is down-regulated in the absence of MDA-9, leading to cell death in GSCs under conditions of anoikis. Our studies confirm a functional link between MDA-9 expression and protective autophagy in GSCs and show that inhibition of MDA-9 reverses protective autophagy and induces anoikis and cell death in GSCs.

scholarly journals TMIC-36. CROSSTALK OF GLIOMA STEM CELLS WITH VASCULAR ENDOTHELIAL CELLS PERSISTS THEIR PRONEURAL PHENOTYPE AND THERAPY RESISTANCE VIA ENDOCAN-CD11A INTERACTION

2017 ◽  
Vol 19 (suppl_6) ◽  
pp. vi251-vi251
Author(s):  
Soniya Bastola ◽  
Marat Pavlyukov ◽  
Yasmin Ghochani ◽  
Hai Yu ◽  
Suojun Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Therapy Resistance ◽  
Glioma Stem Cells ◽  
Vascular Endothelial

scholarly journals EZH2 Protects Glioma Stem Cells from Radiation-Induced Cell Death in a MELK/FOXM1-Dependent Manner

2015 ◽  
Vol 4 (2) ◽  
pp. 226-238 ◽  
Author(s):  
Sung-Hak Kim ◽  
Kaushal Joshi ◽  
Ravesanker Ezhilarasan ◽  
Toshia R. Myers ◽  
Jason Siu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Glioma Stem Cells ◽  
Dependent Manner ◽  
Radiation Induced

Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells

FEBS Journal ◽  
2020 ◽  
Vol 287 (10) ◽  
pp. 2023-2036 ◽  
Author(s):  
Kenta Kuramoto ◽  
Masahiro Yamamoto ◽  
Shuhei Suzuki ◽  
Tomomi Sanomachi ◽  
Keita Togashi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Oxidative Phosphorylation ◽  
Glioma Stem Cells

scholarly journals DDIS-27. TARGETING ATP DOCKING AND P35/P25 BINDING OF CDK5 IN GLIOMA STEM CELLS USING SYNTHETIC INHIBITORS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi69-vi69
Author(s):  
Subhas Mukherjee ◽  
Gary Schiltz ◽  
Matt Clutter ◽  
Rama Mishra ◽  
Cheryl Olson ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Stem Cells ◽  
Therapy Resistance ◽  
Kinase Assay ◽  
Glioma Stem Cells ◽  
New Approach ◽  
Signaling Axis ◽  
In Vitro Kinase Assay ◽  
Target Binding

Abstract The survival advantage of glioma stem cells (GSCs) represents a critical mechanism for growth, therapy resistance and recurrence in glioblastoma. So far, targeting GSCs has not been highly specific, since these cells co-opt the normal developmental signaling pathways. We have demonstrated that the activated CDK5-CREB1 signaling axis regulates GSC self-renewal and also promotes radiation-resistance. Thus targeting CDK5 signaling is highly rational, yet there are challenges. Most of the available CDK5 inhibitors also target other CDKs non-specifically. In collaboration with The Center for Molecular Evolution and Drug Discovery, we are developing novel CDK5 inhibitors that are highly potent and specific. METHODOLOGY: The CKD5-p25 crystal structure (pdb code 1UNL) was used to conduct a virtual high throughput screen (vHTS). A library of 10 million commercially available compounds which had been filtered to ensure they possessed good drug-like properties was screened against the crystal structure. The top 33 compounds based on their predicted target binding, synthetic feasibility and availability were tested in an in vitro kinase assay to measure CDK5 inhibition. RESULTS: Of the 33 potential hit, 11 compounds showed a CDK5 inhibition of < 50 µM. These 11 hits represent 4 distinct chemical scaffolds. Two of them have IC50 < 1 µM, with one compound having an IC50 < 0.4 µM. The vHTS and subsequent in vitro testing have therefore confirmed the identification of several new series of potent CDK5 hit compounds. We are now characterizing the kinase selectivity of our different hit series and evaluating their activity in cell-based assays. This will help focus efforts on the most promising 1–2 scaffolds for further medicinal chemistry optimization to improve the compounds’ potency, selectivity and brain penetration. Ultimately, our optimized compounds will be tested in GBM models to demonstrate their effectiveness in inhibiting CDK5 as a new approach for treating GBM.

scholarly journals Bip inhibition in glioma stem cells promotes radiation-induced immunogenic cell death

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Wei Yang ◽  
Zenghe Xiu ◽  
Yuping He ◽  
Wenpeng Huang ◽  
Yanyan Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Tumor Regression ◽  
Critical Role ◽  
Glioma Stem Cells ◽  
High Dose ◽  
Immunogenic Cell Death ◽  
Radiation Induced ◽  
High Doses ◽  
Molecular Patterns

Abstract Tumor regression in sites distant to the irradiated field are thought to be associated with emission of damage-associated molecular patterns (DAMPs) molecules and generation of immunogenic cell death (ICD). Glioma stem cells (GSCs) are resistant to high doses of radiation, and ultimately select the outgrowth of a more aggressive tumor. This study showed high-dose IR triggered fewer DAMPs molecules exposure and release in GSCs comparing to matched non-GSCs. Downregulation of binding immunoglobulin protein (Bip) promoted IR-mediated endoplasmic reticulum stress to generate DAMPs molecules by PERK and IRE1-α phosphorylation, and increased dendritic cells mature and effector T lymphocytes activation. GSCs treated with Bip knockdown and IR efficiently prevented tumor generation, and reduced post-radiotherapy tumor recurrence. These data suggest that Bip plays a critical role in inhibition of IR-induced ICD in GSCs, and Bip inhibition may be a promising strategy on adjuvant therapy by ameliorating tumor immune microenvironment.

Inducible Loss of the Fanconi Anemia Pathway in iPSC Causes Rapid Cell Cycle Arrest and Apoptosis through ATM/ATR and p53 Signaling

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3528-3528
Author(s):  
Timothy M Chlon ◽  
Elizabeth E Hoskins ◽  
Sonya Ruiz-Torres ◽  
Christopher N Mayhew ◽  
Kathryn A Wikenheiser-Brokamp ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Bone Marrow ◽  
Dna Damage ◽  
Cell Death ◽  
Dna Repair ◽  
Cell Cycle Arrest ◽  
Loss Of Function ◽  
Cycle Arrest ◽  
Repair Pathways

Abstract As the source of all cells in the developing embryo proper, embryonic stem cells (ESC) bear the unique responsibility to prevent mutations from being propagated throughout the entire organism and the germ line. It is likely for this reason that ESC and induced pluripotent stem cells (iPSC) maintain a dramatically lower mutation frequency than cultured somatic cells. Multiple mechanisms for this enhanced genomic surveillance have been proposed, including hypersensitivity of DNA damage response signaling pathways and increased activity of error-free DNA repair pathways, such as homologous recombination. However, the effect of loss of function of DNA repair pathways in these cells remains poorly understood. The Fanconi Anemia (FA) pathway is a DNA repair pathway that is required for the repair of DNA interstrand crosslink damage and also promotes repair of DNA double-strand breaks by homologous recombination . Genetic defects in this pathway cause a disease characterized by bone marrow failure and extreme cancer incidence. Several recent studies have revealed that the FA pathway is required for efficient somatic cell reprogramming to iPSC and suggest that FA cells undergo cell death during this process. Another recent study found that the growth of FA patient-specific iPSC was attenuated with a G2/M arrest when compared to control iPSC, suggesting that these cells arrest upon failed DNA repair. In this study, we sought to determine the effects of acute loss of function of the FA pathway in iPSC through the generation of FA patient-derived iPSC with inducible complementation of the defective FA gene. Fibroblasts were cultured from skin biopsies of multiple FA patients and transduced with a lentiviral vector expressing the complementing FA gene product under DOX-inducible control. Cells were then reprogrammed to iPSC using episomal transfection. These cells formed iPSC colonies only when reprogramming was carried out in the presence of DOX, confirming that the FA pathway is required for efficient reprogramming. Once cell lines were obtained, DOX-dependent FA functionality was verified based on FANCD2 monoubiquitination and nuclear focus formation after treatment with DNA damaging agents. We then cultured the iPSC for extended periods of time in the presence and absence of DOX. Interestingly, the cultures underwent profound cell death and cell cycle arrest within 7 days of DOX-withdrawal and completely failed to expand after one passage. EdU cell cycle analysis confirmed cell cycle arrest in the G2/M phase. Furthermore, cleaved caspase 3 staining confirmed that the number of apoptotic cells increased by 3-fold in the -DOX culture. Despite these effects, cells cultured in both the presence and absence of DOX formed teratomas in nude mice, thus indicating the maintenance of full differentiation capacity in the absence of the FA pathway. In order to determine the mechanisms underlying G2/M arrest and cell death, expression of p53 and its target genes was detected by both western blot analysis and qRT-PCR. Only a slight increase in p53 activation was observed by 7 days post DOX-withdrawal. Furthermore, knockdown of p53 resulted in rescue from apoptosis to normal levels but not rescue from cell cycle arrest. Increased ATM and ATR DNA damage sensor kinase activities were also detected in –DOX cells, concominant with increased phosphorylation of the ATM-target Chk2 and reduced abundance of the G2/M checkpoint protein CDC25A. These results reveal hyperactive DNA damage responses upon FA loss which may underlie the attenuated cell cycle progression of FA-iPSC independent of p53. Remarkably, effects in this FA model system appear equivalent to those responsible for the depletion of HSC in the bone marrow of FA patients. Thus, iPSC models may be useful for future studies of the mechanisms underlying FA stem cell arrest and for the development of therapeutics that alleviate these phenotypes. Disclosures No relevant conflicts of interest to declare.

scholarly journals Transcriptional CDK Inhibitors CYC065 and THZ1 Induce Apoptosis in Glioma Stem Cells Derived from Recurrent GBM

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1182
Author(s):  
Viktorija Juric ◽  
Heiko Düssmann ◽  
Martine L. M. Lamfers ◽  
Jochen H. M. Prehn ◽  
Markus Rehm ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Apoptotic Cell ◽  
Clinical Investigation ◽  
Light Sheet ◽  
Adult Brain ◽  
Glioma Stem Cells ◽  
Stem Cell Markers ◽  
Cdk Inhibitors ◽  
Recurrent Gbm

Glioma stem cells (GSCs) are tumour initiating cells which contribute to treatment resistance, temozolomide (TMZ) chemotherapy and radiotherapy, in glioblastoma (GBM), the most aggressive adult brain tumour. A major contributor to the uncontrolled tumour cell proliferation in GBM is the hyper activation of cyclin-dependent kinases (CDKs). Due to resistance to standard of care, GBMs relapse in almost all patients. Targeting GSCs using transcriptional CDK inhibitors, CYC065 and THZ1 is a potential novel treatment to prevent relapse of the tumour. TCGA-GBM data analysis has shown that the GSC markers, CD133 and CD44 were significantly upregulated in GBM patient tumours compared to non-tumour tissue. CD133 and CD44 stem cell markers were also expressed in gliomaspheres derived from recurrent GBM tumours. Light Sheet Florescence Microscopy (LSFM) further revealed heterogeneous expression of these GSC markers in gliomaspheres. Gliomaspheres from recurrent tumours were highly sensitive to transcriptional CDK inhibitors, CYC065 and THZ1 and underwent apoptosis while being resistant to TMZ. Apoptotic cell death in GSC subpopulations and non-stem tumour cells resulted in sphere disruption. Collectively, our study highlights the potential of these novel CKIs to induce cell death in GSCs from recurrent tumours, warranting further clinical investigation.

scholarly journals Targeting Folate Metabolism Is Selectively Cytotoxic to Glioma Stem Cells and Effectively Cooperates with Differentiation Therapy to Eliminate Tumor-Initiating Cells in Glioma Xenografts

2021 ◽  
Vol 22 (21) ◽  
pp. 11633
Author(s):  
Masashi Okada ◽  
Shuhei Suzuki ◽  
Keita Togashi ◽  
Asuka Sugai ◽  
Masahiro Yamamoto ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
High Sensitivity ◽  
Therapy Resistance ◽  
Folate Metabolism ◽  
Glioma Stem Cells ◽  
Tumor Initiating Cells ◽  
Dismal Prognosis

Glioblastoma (GBM) is one of the deadliest of all human cancers. Developing therapies targeting GBM cancer stem cells or glioma stem cells (GSCs), which are deemed responsible for the malignancy of GBM due to their therapy resistance and tumor-initiating capacity, is considered key to improving the dismal prognosis of GBM patients. In this study, we found that folate antagonists, such as methotrexate (MTX) and pemetrexed, are selectively cytotoxic to GSCs, but not to their differentiated counterparts, normal fibroblasts, or neural stem cells in vitro, and that the high sensitivity of GCSs to anti-folates may be due to the increased expression of RFC-1/SLC19A1, the reduced folate carrier that transports MTX into cells, in GSCs. Of note, in an in vivo serial transplantation model, MTX alone failed to exhibit anti-GSC effects but promoted the anti-GSC effects of CEP1347, an inducer of GSC differentiation. This suggests that folate metabolism, which plays an essential role specifically in GSCs, is a promising target of anti-GSC therapy, and that the combination of cytotoxic and differentiation therapies may be a novel and promising approach to effectively eliminate cancer stem cells.

scholarly journals Glioma Stem Cells and Their Microenvironments: Providers of Challenging Therapeutic Targets

2016 ◽  
Vol 2016 ◽  
pp. 1-20 ◽  
Author(s):  
Elena Codrici ◽  
Ana-Maria Enciu ◽  
Ionela-Daniela Popescu ◽  
Simona Mihai ◽  
Cristiana Tanase
Keyword(s):  
Stem Cells ◽  
Cell Biology ◽  
Malignant Gliomas ◽  
Therapy Resistance ◽  
Metabolic Reprogramming ◽  
Glioma Stem Cells ◽  
Macrophage Colony ◽  
Potential Use ◽  
Macrophage Colony Stimulation Factor

Malignant gliomas are aggressive brain tumors with limited therapeutic options, possibly because of highly tumorigenic subpopulations of glioma stem cells. These cells require specific microenvironments to maintain their “stemness,” described as perivascular and hypoxic niches. Each of those niches induces particular signatures in glioma stem cells (e.g., activation of Notch signaling, secretion of VEGF, bFGF, SDF1 for the vascular niche, activation of HIF2α, and metabolic reprogramming for hypoxic niche). Recently, accumulated knowledge on tumor-associated macrophages, possibly delineating a third niche, has underlined the role of immune cells in glioma progression,viaspecific chemoattractant factors and cytokines, such as macrophage-colony stimulation factor (M-CSF). The local or myeloid origin of this new component of glioma stem cells niche is yet to be determined. Such niches are being increasingly recognized as key regulators involved in multiple stages of disease progression, therapy resistance, immune-escaping, and distant metastasis, thereby substantially impacting the future development of frontline interventions in clinical oncology. This review focuses on the microenvironment impact on the glioma stem cell biology, emphasizing GSCs cross talk with hypoxic, perivascular, and immune niches and their potential use as targeted therapy.

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