The FOXO1 inhibitor AS1842856 triggers apoptosis in glioblastoma multiforme and basal‐like breast cancer cells

Abstract

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.

STAMBPL1 promotes triple-negative breast cancer angiogenesis by upregulating the transcription of GRHL3/HIF1α/VEGFA via FOXO1

“…Our previous studies have also found that DNA damage chemotherapeutic drugs suppress basal-like breast cancer growth by downregulating the transcription of the FOXO1-KLF5 axis [21] . In addition, it has been reported that the FOXO1 inhibitor AS1842856 (a cell-permeable small molecule that directly binds to unphosphorylated FOXO1 protein to block its transcriptional activity) triggers apoptosis in basal-like breast cancer cells [22] , and the FOXO1 inhibitor AS1842856 alone or combined with Onapristone (PR antagonist), blunted phosphorylated PR, and tumorsphere formation in PR-A + (T47D) and PR-B + (MCF7 and BT474) cells [23] .…”