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ERK inhibition in glioblastoma is associated with autophagy activation and tumorigenesis suppression

  • Laboratory Investigation
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Purpose

Autophagy-dependent tumorigenic growth is one of the most commonly reported molecular mechanisms in glioblastoma (GBM) progression. However, the mechanistic correlation between autophagy and GBM is still largely unexplored, especially the roles of autophagy-related genes involved in GBM oncogenesis. In this study, we aimed to explore the genetic alterations that interact with both autophagic activity and GBM tumorigenesis, and to investigate the molecular mechanisms of autophagy involved in GBM cell death and survival.

Method

For this purpose, we systematically explored the alterations of autophagic molecules at the genome level in human GBM samples through deep RNA sequencing. The effect of genetic and pharmacologic inhibition of ERK on GBM growth in vitro and in vivo was researched. An image-based tracking analysis of LC3 using mCherry-eGFP-LC3 plasmid, and transmission electron microscopy were utilized to monitor autophagic flux. Immunoblot analysis was used to measure the related proteins.

Results

MAPK ERK expression was identified as one of the most probable autophagy-related transcriptional responses during GBM growth. The genetic and pharmacologic inhibition of ERK in vivo and in vitro led to cell death, demonstrating its critical role for GBM proliferation and survival. To our surprise, autophagic activities were excessively activated and resulted in cytodestructive effects on GBM cells upon ERK inhibitor treatment. Furthermore, based on the observation of downregulation of mTOR signaling, we speculated the ERK inhibitor-induced GBM cells death might depend on mTOR-mediated pathway, leading to autophagy dysregulation. Accordingly, the in vivo and in vitro experiments revealed that the mTOR inhibitor rapamycin further increased cell mortality and exhibited enhanced antitumor effect on GBM cells when co-treated with the ERK inhibitor.

Conclusion

Our data creatively demonstrated that the autophagy-related regulator ERK maintains autophagic activity during GBM tumorigenesis via mTOR signaling pathway. The pharmacologic inhibition of both mTOR and ERK signaling exhibited synergistic therapeutic effect on GBM growth in vivo and in vitro, which has certain novelty and may provide a potential therapeutic approach for GBM treatment in the future.

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Data availability

All data generated or analyzed during this study are included in this article, which are available from the corresponding author on reasonable request. No additional data are available.

Code availability

Not applicable.

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Authors and Affiliations

  1. Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical University, 469 Zhongshan Street, Dalian, Liaoning Province, People’s Republic of China

    Kang Yang, Xinyu Li, Xu Sun & Jian Yin

  2. The Second Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China

    Lan Luan

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Contributions

The study conception and design were performed by KY and JY. Material preparation, data collection and analysis were performed by KY, LL, XL and XS. The first draft of the manuscript was written by KY. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Jian Yin.

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The study was approved by the Ethics Committee of the second hospital of Dalian Medical University (DMU) and followed the ethical guidelines of Declaration of Helsinki. Written informed consent was obtained from all patients whose tissues were used in this study. Mice were purchased from the Institute of Genome-Engineered Animal Models of DMU and were kept under specific pathogen-free conditions. The study was approved by the Animal Ethics Committee of DMU.

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Yang, K., Luan, L., Li, X. et al. ERK inhibition in glioblastoma is associated with autophagy activation and tumorigenesis suppression. J Neurooncol 156, 123–137 (2022). https://doi.org/10.1007/s11060-021-03896-3

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