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

Ciechomska Iwona Anna; Gielniewski Bartlomiej; Wojtas Bartosz; Kaminska Bozena; Mieczkowski Jakub

doi:10.1038/s12276-020-0479-9

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자료유형: 학술저널

저자정보: Ciechomska Iwona Anna (Nencki Institute of Experimental Biology) Gielniewski Bartlomiej (Nencki Institute of Experimental Biology) Wojtas Bartosz (Nencki Institute of Experimental Biology) Kaminska Bozena (Nencki Institute of Experimental Biology) Mieczkowski Jakub (Nencki Institute of Experimental Biology)

저널정보: 대한생화학·분자생물학회 Experimental and Molecular Medicine Experimental and Molecular Medicine 제52권

발행연도: 2020.8

수록면: 1 - 15 (15page)

DOI: 10.1038/s12276-020-0479-9

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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.

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