EGFR/FOXO3a/BIM signaling pathway determines chemosensitivity of BMP4-differentiated glioma stem cells to temozolomide

Abstract

Accumulating evidence suggests that glioma stem cells (GSCs), which are rare cells characterized by pluripotency and self-renewal ability, are responsible for glioblastoma (GBM) propagation, recurrence and resistance to therapies. Bone morphogenic proteins (BMPs) induce GSC differentiation, which leads to elimination of GSCs and sensitization of glioma to chemotherapeutics. Alterations in the epidermal growth factor receptor (EGFR) gene are detected in more than half of GBMs; however, the role of EGFR in the chemoresistance of GSCs remains unknown. Here, we examined whether EGFR signaling affects BMP4-induced differentiation of GSCs and their response to the alkylating drug temozolomide (TMZ). We show that BMP4 triggers the SMAD signaling cascade in GSCs independent of the EGFR level. BMP4 downregulated the levels of pluripotency markers (SOX2 and OLIG2) with a concomitant induction of an astrocytic marker (GFAP) and a neuronal marker (β-Tubulin III). However, GSCs with different EGFR levels responded differently to treatments. BMP4-induced differentiation did not enhance sensitivity to TMZ in EGFRlow GSCs, in contrast to EGFRhigh GSCs, which underwent apoptosis. We then identified differences in cell cycle regulation. In EGFRlow cells, BMP4-triggered G1 cell cycle arrest which was not detected in EGFRhigh cells. RNA-seq profiles further highlighted transcriptomic alterations and distinct processes characterizing EGFR-dependent responses in the course of BMP4-induced differentiation. We found that the control of BIM (the pro-apoptotic BCL-2 family protein) by the AKT/FOXO3a axis only operated in BMP4-differentiated EGFRhigh cells upon TMZ treatment.

A Novel Role of BIRC3 in Stemness Reprogramming of Glioblastoma

“…BMP4 is strongly associated with GBM stem cell differentiation [ 29 , 30 , 31 ], and has been reported as a potential anti-GBM target [ 32 ]. Since BIRC3 expression is associated with GBM cell self-renewal and stemness maintenance, we wanted to determine if there was any correlation between BIRC3 expression and BMP4 signaling activation.…”

HAX1 maintains the glioma progression in hypoxia through promoting mitochondrial fission

“…Gliomas are known as the most common malignant tumours of the central nervous system (CNS) and express aggressive and malignant progression and high rates of recurrence. 1 , 2 Even though the traditional treatment methods (including surgical resection, radiotherapy and chemotherapy) have made considerable progress, the survival rate of glioma remains at a low level. 3 , 4 , 5 A better understanding of glioma that provides a new potential treatment to glioma needs a breakthrough.…”

Targeting Glioblastoma Stem Cells: A Review on Biomarkers, Signal Pathways and Targeted Therapy

“…Hence, the promotion of GSC differentiation might be a key player in the therapeutic strategies for GBM. The bone morphogenic proteins (BMPs) involved in promoting normal neural precursor differentiation into astrocytes and post-transcriptional modification using miRNA, have been demonstrated to play a positive role in the stem cell niche of the adult brain, increase in GSC differentiation, and suppression of glioblastoma tumorigenicity in vivo , leading to the elimination of GSCs and sensitization of GBM to chemotherapeutics ( 2 , 171 ). Recently, the overexpression of miR-128 or miR-302a has been shown to promote GSC differentiation, enhance senescence mediated by axitinib treatment, and further impair GSC proliferation ( 172 ).…”