Abstract
FOXO factors are tumour suppressor proteins commonly inactivated in human tumours by posttranslational modifications. Furthermore, genetic variation within the FOXO3a gene is consistently associated with human longevity. Therefore, the pharmacological activation of FOXO proteins is considered as an attractive therapeutic approach to treat cancer and age-related diseases. In order to identify agents capable of activating FOXOs, we tested a collection of small chemical compounds using image-based high content screening technology. Here, we report the discovery of LOM612 (compound 1a), a newly synthesized isothiazolonaphthoquinone as a potent FOXO relocator. Compound 1a induces nuclear translocation of a FOXO3a reporter protein as well as endogenous FOXO3a and FOXO1 in U2OS cells in a dose-dependent manner. This activity does not affect the subcellular localization of other cellular proteins including NFkB or inhibit CRM1-mediated nuclear export. Furthermore, compound 1a shows a potent antiproliferative effect in human cancer cell lines.
Highlights
The mammalian forkhead transcription factors of the O class (FOXOs) consists of four proteins, FoxO1, FoxO3, FoxO4 and FoxO6 [1,2]
The nuclear accumulation of green fluorescent protein (GFP) induced by Leptomycin B (LMB), an inhibitor of the CMR-1-dependent nuclear export that covalently binds to a single cysteine residue of the CRM1 protein, was used as a reference and defined as 100% activity. 0.5% DMSO was used as a vehicle control
We report the discovery of a new compound that induces the nuclear translocation of FOXO
Summary
The mammalian forkhead transcription factors of the O class (FOXOs) consists of four proteins, FoxO1, FoxO3, FoxO4 and FoxO6 [1,2]. FoxOs have a characteristic forkhead box DNA binding domain and bind as monomers to their consensus DNA binding sites [3]. FOXO proteins function as transcriptional regulators in the cell nucleus and activate the transcription of genes that are involved in numerous biologically relevant processes such as metabolism, differentiation, proliferation, longevity, and apoptosis [4]. FoxOs are key components of an evolutionary conserved pathway downstream of insulin and insulin-like growth factor receptors.
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