The FOXO1 inhibitor AS1842856 triggers apoptosis in glioblastoma multiforme and basal-like breast cancer cells.
The FOXO1 inhibitor AS1842856 triggers apoptosis in glioblastoma multiforme and basal-like breast cancer cells.
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FOXO1抑制剂AS 1842856触发多形性胶质母细胞瘤和基底样乳腺癌细胞的凋亡。
DOI：
10.1002/2211-5463.13547
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发表时间：
2023-03
期刊：
影响因子：
2.6
通讯作者：
Keniry, Megan
中科院分区：
文献类型：
--
作者：
Flores, David;Lopez, Alma;Udawant, Shreya;Gunn, Bonnie;Keniry, Megan
基底细胞样乳腺癌(BBC)和多形性胶质母细胞瘤(GBM)是预后较差的癌症，缺乏有效的靶向治疗，并且具有胚胎干细胞基因表达的特征。最近，我们的团队和其他人发现叉头盒转录因子FOXO1在BBC和GBM细胞系中促进干细胞基因的表达。鉴于癌症干细胞在促进癌症进展中的关键作用，我们研究了AS1842856(一种细胞渗透性小分子，直接与未磷酸化的FOXO1蛋白结合以阻断转录调控)抑制FOXO1对BBC和GBM细胞活力的影响。我们用浓度增加的AS1842856处理一组BBC和GBM癌细胞，发现集落形成减少。用AS1842856处理BBC和GBM癌细胞后，Fas(Fas细胞表面死亡受体)和BIM(BCL2L11)基因表达增加，细胞凋亡标志物如Annexin V和Propidium iodide阳性表达增加。用另一种FOXO1抑制剂AS1708727或FOXO1 RNAi处理后，Fas也被诱导。这项工作首次表明，靶向BBC和GBM并抑制FOXO1会导致细胞凋亡。这些新的发现可能最终会扩大预后不良癌症的治疗范围。多形性胶质母细胞瘤(GBM)和基底细胞样乳腺癌(BBC)具有FOXO1驱动的胚胎干细胞基因表达特征。用FOXO1抑制剂AS1842856处理GBM和BBC细胞后，促凋亡基因表达增加，细胞凋亡率增加，集落形成减少。这项工作首次表明抑制BBC和GBM中的FOXO1会导致细胞凋亡，这突显了一种新的靶向治疗。
Basal‐like breast cancer (BBC) and glioblastoma multiforme (GBM) are poor‐prognosis cancers that lack effective targeted therapies and harbor embryonic stem gene expression signatures. Recently, our group and others found that forkhead box transcription factor FOXO1 promotes stem gene expression in BBC and GBM cell lines. Given the critical role of cancer stem cells in promoting cancer progression, we examined the impact of FOXO1 inhibition with AS1842856 (a cell‐permeable small molecule that directly binds to unphosphorylated FOXO1 protein to block transcriptional regulation) on BBC and GBM cell viability. We treated a set of BBC and GBM cancer cell lines with increasing concentrations of AS1842856 and found reduced colony formation. Treatment of BBC and GBM cancer cells with AS1842856 led to increases in FAS (FAS cell surface death receptor) and BIM (BCL2L11) gene expression, as well as increased positivity for markers for apoptosis such as annexin V and propidium iodide. Treatment with another FOXO1 inhibitor AS1708727 or FOXO1 RNAi also led to FAS induction. This work is the first to show that targeting BBC and GBM with FOXO1 inhibition leads to apoptosis. These novel findings may ultimately expand the repertoire of therapies for poor‐prognosis cancers. Glioblastoma multiforme (GBM) and basal‐like breast cancer (BBC) harbor FOXO1‐driven embryonic stem gene expression signatures. Treatment of GBM and BBC cells with the FOXO1 inhibitor AS1842856 led to increased pro‐apoptotic gene expression, increased apoptosis, and reduced colony formation. This work is the first to show that inhibiting FOXO1 in BBC and GBM leads to apoptosis, highlighting a novel targeted therapy.
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