EGFR/FOXO3a/BIM signaling pathway determines chemosensitivity of BMP4-differentiated glioma stem cells to temozolomide.
EGFR/FOXO3a/BIM signaling pathway determines chemosensitivity of BMP4-differentiated glioma stem cells to temozolomide.
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EGFR/FOXO 3a/BIM信号通路决定BMP 4分化的胶质瘤干细胞对替莫唑胺的化疗敏感性
DOI：
10.1038/s12276-020-0479-9
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发表时间：
2020-08
影响因子：
12.8
通讯作者：
Mieczkowski J
中科院分区：
文献类型：
--
作者：
Ciechomska IA;Gielniewski B;Wojtas B;Kaminska B;Mieczkowski J
越来越多的证据表明，胶质瘤干细胞（GSC）是一种具有多能性和自我更新能力的稀有细胞，与胶质母细胞瘤（GBM）的增殖、复发和治疗耐药有关。骨形态发生蛋白 (BMP) 诱导 GSC 分化，从而导致 GSC 消除并使神经胶质瘤对化疗药物敏感。在超过一半的 GBM 中检测到表皮生长因子受体 (EGFR) 基因的改变；然而，EGFR 在 GSC 化疗耐药中的作用仍不清楚。在这里，我们检查了 EGFR 信号传导是否影响 BMP4 诱导的 GSC 分化及其对烷化药物替莫唑胺 (TMZ) 的反应。我们发现，BMP4 在 GSC 中触发 SMAD 信号级联，与 EGFR 水平无关。 BMP4 下调多能性标记物（SOX2 和 OLIG2）的水平，同时诱导星形细胞标记物（GFAP）和神经元标记物（β-微管蛋白 III）。然而，具有不同 EGFR 水平的 GSC 对治疗的反应不同。与经历细胞凋亡的 EGFRhigh GSC 相比，BMP4 诱导的分化并未增强 EGFRlow GSC 对 TMZ 的敏感性。然后我们发现了细胞周期调节的差异。在 EGFRlow 细胞中，BMP4 触发 G1 细胞周期停滞，而在 EGFRhigh 细胞中未检测到。 RNA-seq 谱进一步强调了 BMP4 诱导分化过程中转录组的改变和表征 EGFR 依赖性反应的独特过程。我们发现，AKT/FOXO3a 轴对 BIM（促凋亡 BCL-2 家族蛋白）的控制仅在 TMZ 处理后的 BMP4 分化的 EGFRhigh 细胞中起作用。个体神经胶质瘤干细胞（GSC）的特性可能会影响化疗治疗侵袭性脑癌的成功率。 GSC 促进胶质母细胞瘤的肿瘤生长和化疗耐药性。一种潜在的治疗方法是使用骨形态发生蛋白诱导 GSC 分化为危害较小的细胞。一旦 GSC 数量减少，在许多但并非所有情况下，化疗耐药性都会降低。波兰华沙 Nencki 实验生物学研究所的 Jakub Mieczkowski、Bozena Kaminska 和同事对源自患者的胶质母细胞瘤细胞培养物进行了实验。他们发现，GSC 中表皮生长因子受体 (EGFR) 蛋白表达水平高的样本在分化后对化疗药物替莫唑胺的敏感性更高。相反，低水平的EGFR导致分化后维持化疗耐药，这可能解释了一些患者化疗失败的原因。
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. The properties of individual glioma stem cells (GSCs) may influence the success of chemotherapy in tackling aggressive brain cancer. GSCs promote tumor growth and chemotherapy resistance in glioblastoma tumors. One potential treatment approach uses bone morphogenetic proteins to induce GSCs to differentiate into less harmful cells. Once the GSC population has dwindled, chemoresistance reduces in many but not all cases. Jakub Mieczkowski, Bozena Kaminska and co-workers at the Nencki Institute of Experimental Biology in Warsaw, Poland, conducted experiments on patient-derived glioblastoma cell cultures. They found that samples with high expression levels of the epidermal growth factor receptor (EGFR) protein in GSCs showed heightened sensitivity to the chemotherapy drug temozolomide after differentiation. Conversely, low levels of EGFR resulted in chemoresistance being maintained after differentiation, which may explain the failure of chemotherapy in some patients.
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