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Tumor-treating fields induce autophagy by blocking the Akt2/miR29b axis in glioblastoma cells

Oncogene volume 38, pages 6630–6646 (2019)Cite this article

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Abstract

Tumor-treating fields (TTFs) — a type of electromagnetic field-based therapy using low-intensity electrical fields — has recently been characterized as a potential anticancer therapy for glioblastoma multiforme (GBM). However, the molecular mechanisms involved remain poorly understood. Our results show that the activation of autophagy contributes to the TTF-induced anti-GBM activity in vitro or in vivo and GBM patient stem cells or primary in vivo culture systems. TTF-treatment upregulated several autophagy-related genes (~2-fold) and induced cytomorphological changes. TTF-induced autophagy in GBM was associated with decreased Akt2 expression, not Akt1 or Akt3, via the mTOR/p70S6K pathway. An Affymetrix GeneChip miRNA 4.0 Array analysis revealed that TTFs altered the expression of many microRNAs (miRNAs). TTF-induced autophagy upregulated miR-29b, which subsequently suppressed the Akt signaling pathway. A luciferase reporter assay confirmed that TTFs induced miR-29b to target Akt2, negatively affecting Akt2 expression thereby triggering autophagy. TTF-induced autophagy suppressed tumor growth in GBM mouse models subjected to TTFs as determined by positron emission tomography and computed tomography (PET-CT). GBM patient stem cells and a primary in vivo culture system with high Akt2 levels also showed TTF-induced inhibition. Taken together, our results identified autophagy as a critical cell death pathway triggered by TTFs in GBM and indicate that TTF is a potential treatment option for GBM.

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Funding

This work was supported by a National Research Foundation of Korea (NRF) grant (no. NRF-2017R1D1A1B03028923) and a grant from the Korea Institute of Radiological and Medical Sciences (KIRAMS), which was funded by the Ministry of Science, ICT (MSIP) Republic of Korea (50531-2018, 50538-2019).

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  1. These authors contributed equally: Myonggeun Yoon, Sang-Gu Hwang

Authors and Affiliations

  1. Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, 01812, Republic of Korea

    Eun Ho Kim, Yunhui Jo, Mung-Jin Park, Jeong-Yub Kim, Yeon-Joo Lee, Jae-Min Cho, Jeong-Hwa Baek, Jie-Young Song & Sang-Gu Hwang

  2. Department of Bio-Convergence Engineering, Korea University, Seoul, 02842, Republic of Korea

    Yunhui Jo & Myonggeun Yoon

  3. Department of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences, Chiba, Japan

    Sei Sai

  4. Division of RI-Convergence Research, Korea Institute of Radiological and Medical Sciences, Seoul, 01812, Republic of Korea

    Jin Su Kim

  5. Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea

    Seo-Young Kwak

  6. Radiation Non-clinical Center, Division of Radiation Research Infrastructure Operation, Korea Institute of Radiological and Medical Sciences, Seoul, 01812, Republic of Korea

    Youn Kyoung Jeong

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Correspondence to Myonggeun Yoon or Sang-Gu Hwang.

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Our study was approved by the Animal Ethics Committee (KUIACUC-2018-73, 1 June 2018).

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Kim, E.H., Jo, Y., Sai, S. et al. Tumor-treating fields induce autophagy by blocking the Akt2/miR29b axis in glioblastoma cells. Oncogene 38, 6630–6646 (2019). https://doi.org/10.1038/s41388-019-0882-7

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