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

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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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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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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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