Ionizing radiation induces resistant glioblastoma stem-like cells by promoting autophagy via the wnt/β-catenin pathway

Cheng Yu Tsai, Huey Jiun Ko, Chi Ying F. Huang, Ching Yi Lin, Shean Jaw Chiou, Yu Feng Su, Ann Shung Lieu, Joon Khim Loh, Aij Lie Kwan*, Tsung Hsien Chuang, Yi Ren Hong

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Therapeutic resistance in recurrent glioblastoma multiforme (GBM) after concurrent chemoradiotherapy (CCRT) is a challenging issue. Although standard fractionated radiation is essential to treat GBM, it has led to local recurrence along with therapy-resistant cells in the ionizing radiation (IR) field. Lines of evidence showed cancer stem cells (CSCs) play a vital role in therapy resistance in many cancer types, including GBM. However, the molecular mechanism is poorly un-derstood. Here, we proposed that autophagy could be involved in GSC induction for radioresistance. In a clinical setting, patients who received radiation/chemotherapy had higher LC3II expression and showed poor overall survival compared with those with low LC3 II. In a cell model, U87MG and GBM8401 expressed high level of stemness markers CD133, CD44, Nestin, and autophagy marker P62/LC3II after receiving standard fractionated IR. Furthermore, Wnt/β-catenin proved to be a potential pathway and related to P62 by using proteasome inhibitor (MG132). Moreover, pharmacological inhibition of autophagy with BAF and CQ inhibit GSC cell growth by impairing autophagy flux as demonstrated by decrease Nestin, CD133, and SOX-2 levels. In conclusion, we demonstrated that fractionated IR could induce GSCs with the stemness phenotype by P62-mediated autophagy through the Wnt/β-catenin for radioresistance. This study offers a new therapeutic strategy for targeting GBM in the future.

Original languageEnglish
Article number451
Issue number5
StatePublished - May 2021


  • Autophagy
  • CSC
  • GBM
  • GSC
  • Ionizing radiation (IR)
  • Radiation resistance
  • Wnt/β-Catenin


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