mTOR inhibitor temsirolimus and MEK1/2 inhibitor U0126 promote chromosomal instability and cell type-dependent phenotype changes of glioblastoma cells

Stepanenko, Aleksei A.; Andreieva, S. V.; Korets, Kateryna; Mykytenko, Dmytro; Baklaushev, V. P.; Chekhonin, V. P.; Dmitrenko, V. V.

doi:10.1016/j.gene.2015.12.064

Cited by 14 publications

(12 citation statements)

References 74 publications

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“…6). Besides, inhibition of ERK1/2 activation by U0126 does not alter the migratory potential of several glioma cell lines (41,42) as we have also seen in LNT-229 and Tu-132 control cells. Therefore, we suggest that in glioma cells and in the context of sCPE overexpression, the activation of ERK1/2 by a yet unknown receptor provides anti-migratory effects whereas under other circumstances when no or only very low amounts of sCPE are present, phosphorylation of ERK1/2 can induce migration.…”

Section: Discussionsupporting

confidence: 74%

Carboxypeptidase E transmits its anti-migratory function in glioma cells via transcriptional regulation of cell architecture and motility regulating factors

Armento

Ilina

Kaoma

et al. 2017

International Journal of Oncology

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Glioblastoma (GBM), the most frequent and aggressive malignant primary brain tumor, is characterized by a highly invasive growth. In our previous study we showed that overexpression of Carboxypeptidase E (CPE) mitigated glioma cell migration. In the present study we aimed at deciphering the regulatory mechanisms of the secreted form of CPE (sCPE). By transcriptome analysis and inhibition of signaling pathways involved in the regulation of cell growth and motility, we discovered that overexpression of sCPE was accompanied by differential regulation of mRNAs connected to the motility-associated networks, among others FAK, PAK, Cdc42, integrin, STAT3 as well as TGF-β. Especially SLUG was downregulated in sCPE-overexpressing glioma cells, paralleled by reduced expression of matrix-metalloproteinases (MMP) and, in consequence, by decreased cell migration. Expression of SLUG was regulated by ERK since inhibition of ERK reverted sCPE-mediated SLUG downregulation and enhanced cell motility. In a mouse glioma model, overexpression of sCPE significantly prolonged survival. Our results implicate a novel role for sCPE that mainly affects the expression of motility-associated genes via several signal pathways.

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Section: Discussionsupporting

confidence: 74%

Carboxypeptidase E transmits its anti-migratory function in glioma cells via transcriptional regulation of cell architecture and motility regulating factors

Armento

Ilina

Kaoma

et al. 2017

International Journal of Oncology

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“…We used U0126 to inhibit p-ERK expression (Stepanenko et al ., 2016). First, we assessed the SFs of glioma cells treated with or without the p-ERK inhibitor U0126 after RT by clonogenic assay.…”

Section: Resultsmentioning

confidence: 99%

Tetrandrine Exerts a Radiosensitization Effect on Human Glioma through Inhibiting Proliferation by Attenuating ERK Phosphorylation

Zhang

et al. 2017

Biomolecules & Therapeutics

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Tetrandrine (Tet), a bisbenzylisoquinoline alkaloid, has been reported to have a radiosensitization effect on tumors. However, its effects on human glioma and the specific molecular mechanisms of these effects remain unknown. In this study, we demonstrated that Tet has a radiosensitization effect on human glioma cells. It has been hypothesized that Tet has a radiosensitization effect on glioma cells by affecting the glioma cell cycle and DNA repair mechanism and that ERK mediates these activities. Therefore, we conducted detailed analyses of the effects of Tet on the cell cycle by performing flow cytometric analysis and on DNA repair by detecting the expression of phosphorylated H2AX by immunofluorescence. We used western blot analysis to investigate the role of ERK in the effect of Tet on the cell cycle and DNA repair. The results revealed that Tet exerts its radiosensitization effect on glioma cells by inhibiting proliferation and decreasing the expression of phosphorylated ERK and its downstream proteins. In summary, our data indicate that ERK is involved in Tet-induced radiosensitization of glioma cells via inhibition of glioma cell proliferation or of the cell cycle at G0/G1 phase.

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“…In fact, when considering all the properties of stem-like GBM-initiating cells such as cell proliferation, expression of stemness antigens as well as loss of cell aggregation and increased cell migration, all of them are affected by mTOR inhibition [5, 6, 9, 16, 23, 24]. …”

Section: Discussionmentioning

confidence: 99%

“…Previous studies we co-authored, evidenced by cytofluorimetry that these effects in GBM cells are associated with inhibition of cell growth and suppression of cell migration rather than a frank cytotoxicity [5, 23]. In a recent manuscript it was demonstrated that mTOR inhibition as well as temozolomide may produce a phenotypic shift led by gene modulation and altered protein expression [24, 25]. These phenotypic changes were related to cell proliferation, colony formation and migration and can be reproduced by rapamycin-induced altered gene expression.…”

Section: Introductionmentioning

confidence: 99%

Rapamycin promotes differentiation increasing βIII-tubulin, NeuN, and NeuroD while suppressing nestin expression in glioblastoma cells

et al. 2017

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Glioblastoma cells feature mammalian target of rapamycin (mTOR) up-regulation which relates to a variety of effects such as: lower survival, higher infiltration, high stemness and radio- and chemo-resistance. Recently, it was demonstrated that mTOR may produce a gene shift leading to altered protein expression. Therefore, in the present study we administered different doses of the mTOR inhibitor rapamycin to explore whether the transcription of specific genes are modified. By using a variety of methods we demonstrate that rapamycin stimulates gene transcription related to neuronal differentiation while inhibiting stemness related genes such as nestin. In these experimental conditions, cell phenotype shifts towards a pyramidal neuron-like shape owing long branches. Rapamycin suppressed cell migration when exposed to fetal bovine serum (FBS) while increasing the cell adhesion protein phospho-FAK (pFAK). The present study improves our awareness of basic mechanisms which relate mTOR activity to the biology of glioblastoma cells. These findings apply to a variety of effects which can be induced by mTOR regulation in the brain. In fact, the ability to promote neuronal differentiation might be viewed as a novel therapeutic pathway to approach neuronal regeneration.

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mTOR inhibitor temsirolimus and MEK1/2 inhibitor U0126 promote chromosomal instability and cell type-dependent phenotype changes of glioblastoma cells

Cited by 14 publications

References 74 publications

Carboxypeptidase E transmits its anti-migratory function in glioma cells via transcriptional regulation of cell architecture and motility regulating factors

Carboxypeptidase E transmits its anti-migratory function in glioma cells via transcriptional regulation of cell architecture and motility regulating factors

Tetrandrine Exerts a Radiosensitization Effect on Human Glioma through Inhibiting Proliferation by Attenuating ERK Phosphorylation

Rapamycin promotes differentiation increasing βIII-tubulin, NeuN, and NeuroD while suppressing nestin expression in glioblastoma cells

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