Abstract
We analyzed the role of ABCG2, a drug transporter, in determining the sensitivity of glioma stem cells (GSCs) to demethoxycurcumin (DMC). We first demonstrated that ABCG2 is more highly expressed in GSCs than primary astrocytes. Modulation of ABCG2 levels in GSCs by transfection of ABCG2 shRNA or a lentiviral vector encoding ABCG2 revealed an inverse relation between ABCG2 levels and DMC-induced GSC growth inhibition. Suppressing ABCG2 increased DMC-induced apoptosis and G0/G1 cell cycle arrest in GSCs. It also increased levels reactive oxygen species (ROS) in GSCs treated with DMC, resulting in increased cytochrome C and caspase-3 activity. When GSCs transfected with ABCG2 shRNA or overexpressing ABCG2 were xenografted and the tumor-bearing, immunodeficient mice were treated with DMC, ABCG2 expression suppressed the tumor proliferation rate (T/C %). These findings demonstrate that ABCG2 expression is critical for DMC resistance in GSCs and is a potential therapeutic target for GBM.
Highlights
Glioma stem cells (GSCs) are responsible for the recurrence of glioblastoma multiforme (GBM) and insensitivity to Temozolomide (TMZ), the first-line drug for GBM treatment
Immunohistochemical staining of glioma stem cells (GSCs) spheres (Figure 1C) and flow cytometry analysis showed that more than 97% GSC sphere cells were ATP-binding cassette sub-family G member 2 (ABCG2)-positive (Figure 1B). These results demonstrated that ABCG2 was highly expressed in the GSCs and probably played an important role in their function
We found that co-administration of lenti-GFP-ABCG2 shRNA and 30μM DMC for 48h increased cell apoptosis of 12.15% in GSCs-1 and 11% in GSCs-2 based on TUNEL assays (Figure 4B), and 0.28-fold in GSCs-1 and 0.2-fold in GSCs-2 based on Histone-DNA ELISA assays (Figure 4C) compared with 30μM DMC treatment
Summary
Glioma stem cells (GSCs) are responsible for the recurrence of glioblastoma multiforme (GBM) and insensitivity to Temozolomide (TMZ), the first-line drug for GBM treatment. TMZ is a 3-methyl derivative of mitozolomide that forms O6-methylguanine, which inhibits GBM cell proliferation and induces apoptosis and autophagy in glioma cells [2]. Fueyo et al suggested that O6-methyl guanine -DNA methyl transferase (MGMT) was responsible for resistance of glioma cells to TMZ and MGMT expression formed the basis for clinical treatment strategies. Recent studies showed that drug resistance in GSCs was related to ABCG2 and not MGMT [4]. This suggested that the mechanisms of drug resistance in glioma cells and GSCs were different
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