Ionizing Radiation Induces Resistant Glioblastoma Stem-Like Cells by Promoting Autophagy via the Wnt/β-Catenin Pathway

Abstract

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 understood. 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.

Baicalin induces apoptosis and autophagy in human osteosarcoma cells by increasing ROS to inhibit PI3K/Akt/mTOR, ERK1/2 and β-catenin signaling pathways

“…However, our work did not focus on intercellular Ca 2+ in autophagy or the associated signaling pathways. An abundance of data indicates that the PI3K/Akt/mTOR, ERK1/2 and β-catenin signaling pathways are closely related to proliferation, apoptosis and autophagy [70] , [71] , [72] . In addition, extensive studies have reported that accumulating ROS inhibits the PI3K/Akt/mTOR, ERK1/2 and β-catenin pathways, leading to autophagy and apoptosis [36] , [37] , [73] .…”

K-RAS Acts as a Critical Regulator of CD44 to Promote the Invasiveness and Stemness of GBM in Response to Ionizing Radiation

“…Here, we aimed to explore the underlying mechanism that regulates CD44 expression in GBM cells after irradiation treatment. Previously, it was reported that fractionated IR could induce GSCs with the stemness phenotype by P62-mediated autophagy through the Wnt/β-catenin axis [ 38 , 39 ]. In our research, based on our previous study [ 12 ], we found that irradiated GBM cells can upregulate CD44 expression to induce stemness features.…”

The role of A-kinase interacting protein 1 in regulating progression and stemness as well as indicating the prognosis in glioblastoma

“…The possible explanations were as follows: AKIP1 regulated some key oncogenetic pathways, such as Wnt/β-catenin, PI3K/AKT, Notch pathways, etc. These pathways are closely engaged in regulating cancer stemness in GBM [25] , [26] , [27] .…”