PI3K–mTOR Pathway Inhibition Exhibits Efficacy Against High-grade Glioma in Clinically Relevant Mouse Models

Lin, Fan; Gooijer, Mark C. de; Hanekamp, Diana; Chandrasekaran, G.; Buil, Levi C.M.; Thota, Nishita; Sparidans, Rolf W.; Beijnen, Jos H.; Würdinger, Tom; Tellingen, Olaf van

doi:10.1158/1078-0432.ccr-16-1276

Cited by 66 publications

(66 citation statements)

References 43 publications

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“…Moreover, the activation of PI3K/AKT pathway participated in the glioma progression and various biological effects including proliferation, migration, invasion and apoptosis [51, 52]. The PI3K/AKT pathway inhibitors were discovered to exhibit efficacy against glioblastoma in clinically relevant mouse models [53]. In this work, we revealed that CDC25A over-expression activated the PI3K/AKT pathways in GSCs and knockdown of CDC25A manifested the opposite effects.…”

Section: Dicussionmentioning

confidence: 83%

RETRACTED ARTICLE: Linc00152 promotes malignant progression of glioma stem cells by regulating miR-103a-3p/FEZF1/CDC25A pathway

et al. 2017

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BackgroundGlioma is one of the most frequent intracranial malignant tumors. LncRNAs have been identified as new modulators in the origination and progression of glioma.MethodsQuantitative real-time PCR were conducted to evaluate the expression of linc00152 and miRNA-103a-3p in glioma tissues and cells. Western blot were used to determine the expression of FEZF1 and CDC25A in glioma tissues and cells. Stable knockdown of linc00152 or over-expression of miR-103a-3p in glioma stem cells (GSCs) were established to explore the function of linc00152 and miR-103a-3p in GSCs. Further, luciferase reports were used to investigate the correlation between linc00152 and miR-103a-3p. Cell Counting Kit-8, transwell assays, and flow cytometry were used to investigate the function of linc00152 and miR-103a-3p in GSC malignant biological behaviors. ChIP assays were employed to ascertain the correlations between FEZF1 and CDC25A.ResultsLinc00152 was up-regulated in glioma tissues as well as in GSCs. Knockdown of linc00152 inhibited cell proliferation, migration and invasion, while promoted GSC apoptosis. Linc00152 regulated the malignant behavior of GSCs by binding to miR-103a-3p, which functions as a tumor suppressor. In addition, knockdown of linc00152 down-regulated forebrain embryonic zinc finger protein 1 (FEZF1), a direct target of miR-103a-3p which played an oncogenic role in GSCs. FEZF1 elevated promoter activities and up-regulated expression of the oncogenic gene cell division cycle 25A (CDC25A). CDC25A over-expression activated the PI3K/AKT pathways, which regulated the malignant behavior of GSCs.ConclusionsLinc00152/miR-103a-3p/FEZF1/CDC25A axis plays a novel role in regulating the malignant behavior of GSCs, which may be a new potential therapeutic strategy for glioma therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0677-9) contains supplementary material, which is available to authorized users.

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Section: Dicussionmentioning

confidence: 83%

RETRACTED ARTICLE: Linc00152 promotes malignant progression of glioma stem cells by regulating miR-103a-3p/FEZF1/CDC25A pathway

et al. 2017

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“…Taken together, these results suggest that these proteins are not key players in the mechanisms underlying epilepsy. Relating these findings to literature, it appears that 4E‐BP plays distinct roles in TSC‐driven cortical migration during development and in TSC‐driven epilepsy . Upstream of mTORC1, AMPK1 can phosphorylate TSC2 and Raptor, leading to mTORC1 inhibition.…”

Section: Discussionsupporting

confidence: 68%

Effects of antiepileptic drugs in a new TSC/mTOR‐dependent epilepsy mouse model

Koene

Grondelle

Onori

et al. 2019

Ann Clin Transl Neurol

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Objective An epilepsy mouse model for Tuberous Sclerosis Complex (TSC) was developed and validated to investigate the mechanisms underlying epileptogenesis. Furthermore, the possible antiepileptogenic properties of commonly used antiepileptic drugs (AEDs) and new compounds were assessed. Methods Tsc1 deletion was induced in CAMK2A‐expressing neurons of adult mice. The antiepileptogenic properties of commonly used AEDs and inhibitors of the mTOR pathways were assessed by EEG recordings and by molecular read outs. Results Mice developed epilepsy in a narrow time window (10 ± 2 days) upon Tsc1 gene deletion. Seizure frequency but not duration increased over time. Seizures were lethal within 18 days, were unpredictable, and did not correlate to seizure onset, length or frequency, reminiscent of sudden unexpected death in epilepsy (SUDEP). Tsc1 gene deletion resulted in a strong activation of the mTORC1 pathway, and both epileptogenesis and lethality could be entirely prevented by RHEB1 gene deletion or rapamycin treatment. However, other inhibitors of the mTOR pathway such as AZD8055 and PF4708671 were ineffective. Except for ketogenic diet, none of commonly used AEDs showed an effect on mTORC1 activity. Vigabatrin and ketogenic diet treatment were able to significantly delay seizure onset. In contrast, survival was shortened by lamotrigine. Interpretation This novel Tsc1 mouse model is highly suitable to assess the efficacy of antiepileptic and ‐epileptogenic drugs to treat mTORC1‐dependent epilepsy. Additionally, it allows us to study the mechanisms underlying mTORC1‐mediated epileptogenesis and SUDEP. We found that early treatment with vigabatrin was not able to prevent epilepsy, but significantly delayed seizure onset.

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“…As is well recognized, the key role of mTOR is as a repressor of autophagy; the decrease in mTOR activity can effectively initiate the autophagic response in glioma cells [34-36]. Activation of AMPK leads to the inhibition of mTOR, which also propels autophagy [33].…”

Section: Discussionmentioning

confidence: 99%

Isogambogenic Acid Inhibits the Growth of Glioma Through Activation of the AMPK-mTOR Pathway

Zhao

Peng

Shu

et al. 2017

Cell Physiol Biochem

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Background/Aims: Glioma is the most devastating cancer in the brain and has a poor prognosis in adults. Therefore, there is a critical need for novel therapeutic strategies for the management of glioma patients. Isogambogenic acid, an active compound extracted from the Chinese herb Garcinia hanburyi, induces autophagic cell death. Methods: Cell viability was detected with MTT assays. Cell proliferation was assessed using the colony formation assay. Morphological changes associated with autophagy and apoptosis were tested by TEM and Hoechst staining, respectively. The apoptosis rate was measured by flow cytometry. Western blot, immunofluorescence and immunohistochemical analyses were used to detect protein expression. U87-derived xenografts were established for the examination of the effect of isogambogenic acid on glioma growth in vivo. Results: Isogambogenic acid induced autophagic death in U87 and U251 cells, and blocking late-stage autophagy markedly enhanced the antiproliferative activities of isogambogenic acid. Moreover, we observed the activation of AMPK-mTOR signalling in isogambogenic acid-treated glioma cells. Furthermore, the activation of AMPK or the inhibition of mTOR augmented isogambogenic acid-induced autophagy. Inhibition of autophagy attenuated apoptosis in isogambogenic acid-treated glioma cells. Finally, isogambogenic acid inhibited the growth of U87 glioma in vivo. Conclusion: Isogambogenic acid inhibits the growth of glioma via activation of the AMPK-mTOR signalling pathway, which may provide evidence for future clinical applications in glioma therapy.

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PI3K–mTOR Pathway Inhibition Exhibits Efficacy Against High-grade Glioma in Clinically Relevant Mouse Models

Cited by 66 publications

References 43 publications

RETRACTED ARTICLE: Linc00152 promotes malignant progression of glioma stem cells by regulating miR-103a-3p/FEZF1/CDC25A pathway

RETRACTED ARTICLE: Linc00152 promotes malignant progression of glioma stem cells by regulating miR-103a-3p/FEZF1/CDC25A pathway

Effects of antiepileptic drugs in a new TSC/mTOR‐dependent epilepsy mouse model

Isogambogenic Acid Inhibits the Growth of Glioma Through Activation of the AMPK-mTOR Pathway

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