Glioma‐derived cancer stem cells are hypersensitive to proteasomal inhibition

Yoo, Youngdong; Lee, Dong Hoon; Cha-Molstad, Hyunjoo; Kim, Hyungsin; Mun, Su Ran; Ji, Changhoon; Park, Seong Hye; Sung, Kyung Rim; Choi, Seung Ah; Hwang, Joonsung; Park, Deric M.; Kim, Seung Ki; Park, Kyung Jae; Kang, Sung Ho; Oh, Sang Cheul; Ciechanover, Aaron; Kim, Bo Yeon; Kwon, Yong Tae

doi:10.15252/embr.201642360

Cited by 29 publications

(23 citation statements)

References 55 publications

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“…Glioma, a kind of malignancy arising from glial cells in the brain, is the most common malignant tumours occurring in the central nervous system and accounting for 78% of intracranial primary tumours 1, 2. Glioma usually exhibits a series of malignant features, including extensive, rapid and aggressive progression, resistance to surgery, radiotherapy and chemotherapy, all of which lead to the poor prognosis for most patients 3.…”

Section: Introductionmentioning

confidence: 99%

Retracted: MircoRNA‐1275 promotes proliferation, invasion and migration of glioma cells via SERPINE1

Wang

Wen

et al. 2018

J Cellular Molecular Medi

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This study was designed to explore the relationship between miR‐1275 and SERPINE1 and its effects on glioma cell proliferation, migration, invasion and apoptosis. Differentially expressed miRNAs and mRNAs in glioma tissues were screened out by bioinformatic analysis. Dual‐luciferase reporter gene assay was used to validate the targeted relationship between miR‐1275 and SERPINE1. qRT‐PCR was used to detect the expression of miR‐1275 and SERPINE1 in glioma tissues. The expressions of SERPINE1 and p53 pathway‐related proteins in glioma cells were detected by western blot. Glioma cell proliferation, apoptosis, migration and invasion were respectively detected by CCK‐8 assay, flow cytometry, wound healing assay and transwell assay. Tumour xenograft model was developed to study the influence of miR‐1275 and SERPINE1 on glioma growth in vivo. The results of microarray analysis, qRT‐PCR and western blot showed that miR‐1275 was low‐expressed while SERPINE1 was high‐expressed in glioma. Dual‐luciferase assay showed that miR‐1275 could bind to SERPINE1. Overexpression of miR‐1275 could promote the p53 pathway‐related proteins’ expression. Highly expressed miR‐1275 could repress the migration, proliferation and invasion of glioma cells while highly expressed SERPINE1 had inverse effects. Tumour xenograft showed that up‐regulated miR‐1275 or down‐regulated SERPINE1 could repress glioma growth in vivo. Up‐regulation of miR‐1275 activated p53 signalling pathway via regulating SERPINE1 and therefore suppressed glioma cell proliferation, invasion and migration, whereas promoted cell apoptosis.

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Section: Introductionmentioning

confidence: 99%

Retracted: MircoRNA‐1275 promotes proliferation, invasion and migration of glioma cells via SERPINE1

Wang

Wen

et al. 2018

J Cellular Molecular Medi

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“…It should be noted here that the therapeutic arsenal of oncologists also includes hyperthermia and inhibitors of proteasomes (e.g., bortezomib); CSCs were shown to be very sensitive to either of these exposures [172,173] and co-treatments with hyperthermia or proteasome inhibitors are suggested for sensitizing CSCs to chemotherapy and radiotherapy. The sensitizing effects appear to be due to the accumulation of misfolded proteins in heated or proteasome inhibitor-treated CSCs because these excess misfolded proteins recruit cytosolic chaperones, which thus become unable to maintain the chaperone-dependent features of CSCs, such as chemoresistance and radioresistance.…”

Section: Hsf1 and Hsf1-activating Exposurementioning

confidence: 99%

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Kabakov

Yakimova

Matchuk

2020

Cells

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Cancer stem cells (CSCs) are a great challenge in the fight against cancer because these self-renewing tumorigenic cell fractions are thought to be responsible for metastasis dissemination and cases of tumor recurrence. In comparison with non-stem cancer cells, CSCs are known to be more resistant to chemotherapy, radiotherapy, and immunotherapy. Elucidation of mechanisms and factors that promote the emergence and existence of CSCs and their high resistance to cytotoxic treatments would help to develop effective CSC-targeting therapeutics. The present review is dedicated to the implication of molecular chaperones (protein regulators of polypeptide chain folding) in both the formation/maintenance of the CSC phenotype and cytoprotective machinery allowing CSCs to survive after drug or radiation exposure and evade immune attack. The major cellular chaperones, namely heat shock proteins (HSP90, HSP70, HSP40, HSP27), glucose-regulated proteins (GRP94, GRP78, GRP75), tumor necrosis factor receptor-associated protein 1 (TRAP1), peptidyl-prolyl isomerases, protein disulfide isomerases, calreticulin, and also a transcription heat shock factor 1 (HSF1) initiating HSP gene expression are here considered as determinants of the cancer cell stemness and potential targets for a therapeutic attack on CSCs. Various approaches and agents are discussed that may be used for inhibiting the chaperone-dependent development/manifestations of cancer cell stemness.

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“…Multiple studies have confirmed the existence of CSCs in glioma, or glioma stem cells (GSCs), which are capable of self-renewal, extensive proliferation, and multi-lineage differentiation [ 9 , 14 , 19 ]. These studies have demonstrated that the rare population of GSCs is necessary and sufficient to initiate, maintain, and recapitulate the phenotype of original glioma in immune-compromised mice, and when GSCs are eliminated from the bulk tumor mass, tumor growth is inhibited [ 36 , 37 ]. Therefore, GSCs could play a pivotal role in glioma development in human, and these cells seem to be a promising target for glioma therapies [ 38 ].…”

Section: Introductionmentioning

confidence: 99%

Adenovirus infection promotes the formation of glioma stem cells from glioblastoma cells through the TLR9/NEAT1/STAT3 pathway

et al. 2020

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Background: Glioma stem cells (GSCs) are glioma cells with stemness and are responsible for a variety of malignant behaviors of glioma. Evidence has shown that signals from tumor microenvironment (TME) enhance stemness of glioma cells. However, identification of the signaling molecules and underlying mechanisms has not been completely elucidated. Methods: Human samples and glioma cell lines were cultured in vitro to determine the effects of adenovirus (ADV) infection by sphere formation, RT-qPCR, western blotting, FACS and immunofluorescence. For in vivo analysis, mouse intracranial tumor model was applied. Bioinformatics analysis, gene knockdown by siRNA, RT-qPCR and western blotting were applied for further mechanistic studies. Results: Infection of patient-derived glioma cells with ADV increases the formation of tumor spheres. ADV infection upregulated stem cell markers and in turn promoted the capacities of self-renewal and multi-lineage differentiation of the infected tumor spheres. These ADV infected tumor spheres had stronger potential to form xenograft tumors in immune-compromised mice. GSCs formation could be promoted by ADV infection via TLR9, because TLR9 was upregulated after ADV infection, and knockdown of TLR9 reduced ADV-induced GSCs. Consistently, MYD88, as well as total STAT3 and phosphorylated (p-)STAT3, were also upregulated in ADV-induced GSCs. Knockdown of MYD88 or pharmaceutical inhibition of STAT3 attenuated stemness of ADV-induced GSCs. Moreover, we found that ADV infection upregulated lncRNA NEAT1. Knockdown of NEAT1 impaired stemness of ADV-induced GSCs. Lastly, HMGB1, a damage associated molecular pattern (DAMP) that triggers TLR signaling, also upregulated stemness markers in glioma cells.

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Glioma‐derived cancer stem cells are hypersensitive to proteasomal inhibition

Abstract: Although proteasome inhibitors (PIs) are used as anticancer drugs to treat various cancers, their relative therapeutic efficacy on stem cells vs. bulk cancers remains unknown. Here, we show that stem

Cited by 29 publications

References 55 publications

Retracted: MircoRNA‐1275 promotes proliferation, invasion and migration of glioma cells via SERPINE1

Retracted: MircoRNA‐1275 promotes proliferation, invasion and migration of glioma cells via SERPINE1

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Adenovirus infection promotes the formation of glioma stem cells from glioblastoma cells through the TLR9/NEAT1/STAT3 pathway

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