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IDH1 mutation activates mTOR signaling pathway, promotes cell proliferation and invasion in glioma cells

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Abstract

Background

Glioma is the most common type of brain tumors and isocitrate dehydrogenase (IDH1) gene is the most prominent molecular marker about the disease prognosis, response to therapy and patient survival. There are conflicting data about the effect of IDH1 mutation on glial cell proliferation, invasion and migration characteristics. The effect of IDH1 mutation on mTOR signaling pathway, which has key roles in tumorigenesis process, is limited and previous data is controversial. We aimed to explore the effect of wild type and mutant IDH1 overexpression on glioma cells and investigated the correlation with mTOR signaling pathway associated genes.

Methods and Results

U87-MG and A172 cells were transfected with different IDH1 mutant gene overexpressing (R132H, R132L, R132S, R132C) viral vectors. Cell proliferation, cell invasion and migration analysis as well as quantitative PCR analysis with the mutant glioma cell lines were performed. Forty-two patient derived glioma cells were obtained from patients with different glioma subtypes and cancer cells were enriched by culturing cells. Overexpression of both mutant and wild type IDH1 gene promoted the cell proliferation, but only IDH1 mutation increased cell invasion and migration. The expression of IDH1 mutation activated mTOR signaling via upregulation of WNTA, PRKAA2, GSK3B and MTOR genes as well as phosphorylated mTOR protein level.

Conclusions

Our results highlighted IDH1 mutation upregulate mTOR signaling pathway and promote cell proliferation, invasion and migration.

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Data Availability

All data generated or analyzed during this study are included in this published article/as supplementary information files. Raw results data files can be shared upon request.

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Acknowledgements

This study was funded by Bahcesehir University (BAU), Scientific Research Projects Council, (Project number BAP.2018 − 2.01), and The Scientific and Technological Research Council of Turkey (TUBITAK, project number 118S539).

Funding

This study was funded by Bahcesehir University (BAU), Scientific Research Projects Council, (Project number BAP.2018 − 2.01), and The Scientific and Technological Research Council of Turkey (TUBITAK, project number 118S539).

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Authors and Affiliations

  1. School of Medicine, Medical Biology Department, Bahcesehir University, Istanbul, Turkey

    Timucin Avsar

  2. Graduate School, Neuroscience Program, Bahcesehir University, Istanbul, Turkey

    Timucin Avsar, Tansu Bilge Kose, Muhammed Deniz Oksal, Gizem Turan & Turker Kilic

  3. School of Medicine, Neurosurgery Department, Bahcesehir University, Istanbul, Turkey

    Turker Kilic

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  1. Timucin Avsar
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  2. Tansu Bilge Kose
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Contributions

TA and TBK conceived and designed the study and wrote the manuscript. TA, TBK, MDO and GT participated in data acquisition, analysis and interpretation of data. TK provided the tumor samples and patient information and participated in critical discussions. Also, all authors and acknowledged contributors have read and approved the manuscript and state that the content of this manuscript, in part or in full, has not been published elsewhere in any form. Authors stated their consent for participation and publication of the study.

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Correspondence to Timucin Avsar.

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Conflict of interests

The authors have no personal, financial or institutional interest in any of the methods, materials, or devices described in this article. Authors declare no conflict of interests.

Ethical Standards

This study was approved by Ethical Committee of Bahcesehir University, School of Medicine. All the procedures were performed regarding ethical adherence. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent: Informed consent was obtained from all individual participants included in the study.

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Avsar, T., Kose, T.B., Oksal, M.D. et al. IDH1 mutation activates mTOR signaling pathway, promotes cell proliferation and invasion in glioma cells. Mol Biol Rep 49, 9241–9249 (2022). https://doi.org/10.1007/s11033-022-07750-1

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