Tumor-treating fields induce autophagy by blocking the Akt2/miR29b axis in glioblastoma cells
- Authors
- Kim, Eun Ho; Jo, Yunhui; Sai, Sei; Park, Mung-Jin; Kim, Jeong-Yub; Kim, Jin Su; Lee, Yeon-Joo; Cho, Jae-Min; Kwak, Seo-Young; Baek, Jeong-Hwa; Jeong, Youn Kyoung; Song, Jie-Young; Yoon, Myonggeun; Hwang, Sang-Gu
- Issue Date
- 26-9월-2019
- Publisher
- NATURE PUBLISHING GROUP
- Citation
- ONCOGENE, v.38, no.39, pp.6630 - 6646
- Indexed
- SCIE
SCOPUS
- Journal Title
- ONCOGENE
- Volume
- 38
- Number
- 39
- Start Page
- 6630
- End Page
- 6646
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/62834
- DOI
- 10.1038/s41388-019-0882-7
- ISSN
- 0950-9232
- 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 (similar to 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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