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

Eun Ho Kim, Yunhui Jo, Sei Sai, Mung Jin Park, Jeong Yub Kim, Jin Su Kim, Yeon Joo Lee, Jae Min Cho, Seo Young Kwak, Jeong Hwa Baek, Youn Kyoung Jeong, Jie Young Song, Myonggeun Yoon, Sang Gu Hwang

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5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)6630-6646
Number of pages17
JournalOncogene
Volume38
Issue number39
DOIs
Publication statusPublished - 2019 Sep 26

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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  • Cite this

    Kim, E. H., Jo, Y., Sai, S., Park, M. J., Kim, J. Y., Kim, J. S., Lee, Y. J., Cho, J. M., Kwak, S. Y., Baek, J. H., Jeong, Y. K., Song, J. Y., Yoon, M., & Hwang, S. G. (2019). Tumor-treating fields induce autophagy by blocking the Akt2/miR29b axis in glioblastoma cells. Oncogene, 38(39), 6630-6646. https://doi.org/10.1038/s41388-019-0882-7