scholarly journals STEM-04. NICARDIPINE SENSITIZES APOPTOSIS OF GLIOMA STEM CELLS INDUCED BY TEMOZOLOMIDE THROUGH INHIBITING AUTOPHAGY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi234-vi234
Author(s):  
Jun Dong ◽  
Jia Shi
Keyword(s):  
Stem Cells ◽  
Cell Apoptosis ◽  
Mtor Inhibitor ◽  
Glioma Stem Cells ◽  
Chemotherapeutic Drugs ◽  
Phosphorylation Level ◽  
Stem Cell Lines ◽  
Underlying Mechanisms ◽  
Mtor Activity ◽  
Therapy Of Hypertension

Abstract BACKGROUND Glioma stem cells (GSCs) play an important role in tumor progression and recurrence. Currently, treatments of glioma are limited mainly due to strong tolerance of GSCs against conventional chemotherapeutic drugs such as temozolomide. Nicardipine, a calcium antagonist, is commonly used in the therapy of hypertension, which is recently repurposed in the comprehensive strategies against gliomas in our previous studies. Here, we explored the cytotoxic sensitization effect of nicardipine combining temozolomide and the underlying mechanisms. METHODS Two human glioma stem cell lines were applied and treated with nicardipine, temozolomide, and combination of both, respectively. Cell viability was detected by CCK-8, cell apoptosis was analyzed by flow cytometry, and immunoblot was used to detect autophagic-releated proteins including p62, LC3 and mTOR. The mTOR agonists and inhibitors were applied to further evaluate whether nicardipine inhibits autophagy via mTOR pathway. RESULTS GSCs had strong tolerance against temozolomide while nicardipine could significantly inhibit the viaibility of GSCs and promote cell apoptosis when acting together with temozolomide, indicating that nicardipine could sensitize the toxicity of temozolomide. Furthermore, both temozolomide and nicardipine could inhibit autophagy, and the effects of nicardipine was more prominent, suggesting that nicardipine might enhance GSCs apoptosis induced by temozolomide through inhibiting autophagy. Further molecular studies showed that the cytotoxic sensitization effects of nicardipine was induced through activation of the phosphorylation level of mTOR, which was abolished with the treatment of rapamycin, a mTOR inhibitor. CONCLUSION Our results suggested that nicardipine could sensitize apoptosis of glioma stem cells induced by temozolomide through inhibiting autophagy, which was mediated by activation of mTOR activity.

scholarly journals SMURF2 phosphorylation at Thr249 modifies the stemness and tumorigenicity of glioma stem cells by regulating TGF-β receptor stability

2021 ◽  
Author(s):  
Manami Hiraiwa ◽  
Kazuya Fukasawa ◽  
Takashi Iezaki ◽  
Hemragul Sabit ◽  
Tetsuhiro Horie ◽  
...  
Keyword(s):  
Stem Cells ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Glioma Stem Cells ◽  
Self Renewal ◽  
Ubiquitin Protein Ligase ◽  
Phosphorylation Level ◽  
Ubiquitin Ligase Activity ◽  
Β Receptor ◽  
Underlying Mechanisms

Abstract Glioma stem cells (GSCs) contribute to the pathogenesis of glioblastoma, the most malignant form of glioma. The implication and underlying mechanisms of SMAD specific E3 ubiquitin protein ligase 2 (SMURF2) on the GSC phenotypes remain unknown. We previously demonstrated that SMURF2 phosphorylation at Thr249 (SMURF2Thr249) activates its E3 ubiquitin ligase activity. Here, we demonstrate that SMURF2Thr249 phosphorylation plays an essential role in maintaining GSC stemness and tumorigenicity. SMURF2 silencing augmented the self-renewal potential and tumorgenicity of patient-derived GSCs. The SMURF2Thr249 phosphorylation level was low in human glioblastoma pathology specimens. Introduction of the SMURF2T249A mutant resulted in increased stemness and tumorgenicity of GSCs, recapitulating the SMURF2 silencing. Moreover, the inactivation of SMURF2Thr249 phosphorylation increases TGF-β receptor (TGFBR) protein stability. Indeed, TGFBR1 knockdown markedly counteracted the GSC phenotypes by SMURF2T249A mutant. These findings highlight the importance of SMURF2Thr249 phosphorylation in maintaining GSC phenotypes, thereby demonstrating a potential target for GSC-directed therapy.

scholarly journals SMURF2 phosphorylation at Thr249 modifies the stemness and tumorigenicity of glioma stem cells by regulating TGF-β receptor stability

2021 ◽  
Author(s):  
Manami Hiraiwa ◽  
Kazuya Fukasawa ◽  
Takashi Iezaki ◽  
Hemragul Sabit ◽  
Tetsuhiro Horie ◽  
...  
Keyword(s):  
Stem Cells ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Glioma Stem Cells ◽  
Self Renewal ◽  
Ubiquitin Protein Ligase ◽  
Phosphorylation Level ◽  
Ubiquitin Ligase Activity ◽  
Β Receptor ◽  
Underlying Mechanisms

AbstractGlioma stem cells (GSCs) contribute to the pathogenesis of glioblastoma, the most malignant form of glioma. The implication and underlying mechanisms of SMAD specific E3 ubiquitin protein ligase 2 (SMURF2) on the GSC phenotypes remain unknown. We previously demonstrated that SMURF2 phosphorylation at Thr249 (SMURF2Thr249) activates its E3 ubiquitin ligase activity. Here, we demonstrate that SMURF2Thr249 phosphorylation plays an essential role in maintaining GSC stemness and tumorigenicity. SMURF2 silencing augmented the self-renewal potential and tumorgenicity of patient-derived GSCs. The SMURF2Thr249 phosphorylation level was low in human glioblastoma pathology specimens. Introduction of the SMURF2T249A mutant resulted in increased stemness and tumorgenicity of GSCs, recapitulating the SMURF2 silencing. Moreover, the inactivation of SMURF2Thr249 phosphorylation increases TGF-β receptor (TGFBR) protein stability. Indeed, TGFBR1 knockdown markedly counteracted the GSC phenotypes by SMURF2T249A mutant. These findings highlight the importance of SMURF2Thr249 phosphorylation in maintaining GSC phenotypes, thereby demonstrating a potential target for GSC-directed therapy.

Abstract 2945: Arsenic trioxide sensitizes glioma stem cells to brain penetrant PI3K and mTOR inhibitor GDC-0084

2018 ◽  
Author(s):  
Jianwen Dong ◽  
Emmanuel Martinez-Ledesma ◽  
Nghi Nguyen ◽  
Caroline Carrillo ◽  
Yuji Piao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Arsenic Trioxide ◽  
Mtor Inhibitor ◽  
Glioma Stem Cells

scholarly journals Proton beam radiation induces DNA damage and cell apoptosis in glioma stem cells through reactive oxygen species

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
R. Alan Mitteer ◽  
Yanling Wang ◽  
Jennifer Shah ◽  
Sherika Gordon ◽  
Marcus Fager ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Stem Cells ◽  
Dna Damage ◽  
Proton Beam ◽  
Cell Apoptosis ◽  
Reactive Oxygen ◽  
Glioma Stem Cells ◽  
Oxygen Species ◽  
Beam Radiation ◽  
Proton Beam Radiation

scholarly journals NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, enhances the radiosensitivity of human glioma stem cells in vitro

2013 ◽  
Vol 34 (5) ◽  
pp. 681-690 ◽  
Author(s):  
Wen-juan Wang ◽  
Lin-mei Long ◽  
Neng Yang ◽  
Qing-qing Zhang ◽  
Wen-jun Ji ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mtor Inhibitor ◽  
Glioma Stem Cells ◽  
Human Glioma

scholarly journals A Ploidy Increase Promotes Sensitivity of Glioma Stem Cells to Aurora Kinases Inhibition

2019 ◽  
Vol 2019 ◽  
pp. 1-15
Author(s):  
Chiara Cilibrasi ◽  
Andrèe Guzzi ◽  
Riccardo Bazzoni ◽  
Gabriele Riva ◽  
Massimiliano Cadamuro ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Lines ◽  
Resistant Cell ◽  
Mitotic Exit ◽  
Glioma Stem Cells ◽  
Sensitive Cell ◽  
Mutation Status ◽  
Main Determinant ◽  
Aurora Kinases ◽  
Stem Cell Lines

Glioma stem cells account for glioblastoma relapse and resistance to conventional therapies, and protein kinases, involved in the regulation of the mitotic machinery (i.e., Aurora kinases), have recently emerged as attractive therapeutic targets. In this study, we investigated the effect of Aurora kinases inhibition in five glioma stem cell lines isolated from glioblastoma patients. As expected, cell lines responded to the loss of Aurora kinases with cytokinesis failure and mitotic exit without cell division. Surprisingly, this resulted in a proliferative arrest in only two of the five cell lines. These sensitive cell lines entered a senescent/autophagic state following aberrant mitotic exit, while the non-sensitive cell lines continued to proliferate. This senescence response did not correlate with TP53 mutation status but only occurred in the cell lines with the highest chromosome content. Repeated rounds of Aurora kinases inhibition caused a gradual increase in chromosome content in the resistant cell lines and eventually caused a similar senescence response and proliferative arrest. Our results suggest that a ploidy threshold is the main determinant of Aurora kinases sensitivity in TP53 mutant glioma stem cells. Thus, ploidy could be used as a biomarker for treating glioma patients with Aurora kinases inhibitors.

scholarly journals Nicardipine sensitizes temozolomide by inhibiting autophagy and promoting cell apoptosis in glioma stem cells

Aging ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 6820-6831 ◽  
Author(s):  
Jia Shi ◽  
Xuchen Dong ◽  
Haoran Li ◽  
Haiyang Wang ◽  
Qianqian Jiang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Apoptosis ◽  
Glioma Stem Cells

scholarly journals CBMS-12 PENTAMIDINE; TRANSLATIONAL RESEARCH FOR A NEW CHEMOTHERAPY TARGETING ON GLIOMA CELLS AND GLIOMA STEM CELLS USING DRUG REPOSITIONING

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii6-ii7
Author(s):  
Sho Tamai ◽  
Sabit Hemragul ◽  
Jiapaer Shabierjiang ◽  
Guangtao Zhang ◽  
Jiakang Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Lines ◽  
Glioma Cell ◽  
Drug Repositioning ◽  
Glioma Cells ◽  
Therapeutic Drug ◽  
Glioma Stem Cells ◽  
Glioma Cell Lines ◽  
Proliferation Ability ◽  
Stem Cell Lines

Abstract INTRODUCTION Glioblastoma (GBM) is primary malignant brain tumor with poor prognosis. Despite aggressive chemoradiotherapies, GBM has resistance and finally relapses. Recently, it is revealed that glioma stem cells (GSCs) are forming tumors and induce the recurrence. However, there is no effective therapy for GSCs. Herein, we newly identified pentamidine, an antiprotozoal drug, is effective for not only glioma cells but also GSCs by using drug repositioning approach. METHOD We used two glioma cell lines, A172 and T98, and patient-derived glioma stem cell lines KGS01, KGS07 which were established at Kanazawa University. We investigated proliferation ability, stemness and intracellular signal change by proliferation assay, sphere forming assay and western blotting, respectively. RESULT Proliferation ability was prohibited by pentamidine in both glioma cell lines and GSC lines. The half maximal inhibitory concentrations were 5–10 μM in glioma cell lines and 1–5 μM in GSC lines. Sphere forming assay revealed that size and number of spheres were reduced in both GSC lines, depending on concentration of pentamidine. In all cell lines, phosphorylation of extracellular signal-related kinase (ERK) and signal transducer and activator of transcription 3 (STAT3) were suppressed by pentamidine. DISCUSSION Pentamidine is known as the therapeutic drug for pneumocystis jirovecii. In this study, pentamidine suppressed proliferation activity in all cell lines, and stemness in both GSCs. Previous papers revealed pentamidine had anti-tumor effects for some types of tumor cell lines, however, therapeutic effect for tumor stem cells have never been mentioned. CONCLUSION These results suggest that pentamidine would be therapeutic drug for not only glioma cells but also GSCs by suppressing phosphorylation of ERK and STAT3.

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