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XMD8-92 and JWG-045 exhibit anti-ferroptotic activities, independently of inhibiting ERK5

ABSTRACT: Extracellular-regulated protein kinase 5 (ERK5) is a promising target in cancer therapy, and several ERK5 inhibitors have been developed. In this study, we observed that the inhibitors XMD8-92 and JWG-045 exhibited n anti-ferroptotic activity in breast cancer cells, which was not detected with two other ERK5 inhibitors JWG-071, BAY-885, or the MEK5 inhibitor BIX02189. Using CRISPR-mediated gene editing, we generated ERK5- eficient breast cancer cells and found that XMD8-92 and JWG-045 protected these cells from ferroptosis, indicating clear off-target effects of these inhibitors. RNA sequencing revealed that XMD8-92 might influence erroptosis through the regulation of the oxidative stress-related genes KEAP1 and GCH1. Collectively, these results demonstrate that XMD8-92 and JWG-045 can act independently of ERK5 inhibition, underscoring the mportance of using more specific inhibitors, such as JWG-071, BAY-885, or BIX02189, to evaluate the role of ERK5 signalling in cancer. Furthermore, our data emphasise the critical need for combining bioinformatics nd experimental validation to correctly assign functional roles to specific proteins in biological processes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE302031 | GEO | 2025/07/09

REPOSITORIES: GEO

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Project description:Cancer cell motility and invasiveness are fundamental characteristics of the malignant phenotype and are regulated through diverse signaling networks involving kinases and transcription factors. In this study, we identify a nuclear hormone receptor (ERα)-protein kinase (ERK5)-cofilin (CFL1) network that specifies the degree of breast cancer cell aggressiveness through coupling of actin reorganization and hormone receptor-mediated transcription. Using dominant negative and constitutively active forms, as well as small molecule inhibitors of ERK5 and MEK5, we show that hormone activation of estrogen receptor-α determines the nuclear versus cytoplasmic localization of the MAPK family member ERK5, which functions as a coregulator of ERα-gene transcription. Notably, ERK5 works with the actin remodeling protein, CFL1, and upon hormone exposure both became localized to transcription factories in the nucleus, verified by immunofluorescence and proximity ligation assays. Both factors facilitated PAF1 recruitment to the RNA Pol II complex and both ERK5 and CFL1 were required for regulation of gene transcription. By contrast, in cells lacking ERα, ERK5 and CFL1 localized to cytoplasmic membrane regions of high actin remodeling, promoting cell motility and invasion, thereby revealing a mechanism likely to contribute to the generally poorer prognosis of ERα-negative breast cancers. Our study uncovers the dynamic interplay of nuclear receptor-mediated transcription and actin reorganization in phenotypes of breast cancer aggressiveness, and highlights new prognostic biomarkers and suggests novel approaches for developing targeted therapies to moderate cancer aggressiveness. MCF-7 human breast adenocarcinoma cells were tranfected with control, and ERK5 siRNA for 72 hours and treated with 0.1% EtOH (Vehicle) or 10 nM E2 for 24 hours, and cDNA microarray analyses were carried out using Affymetrix [HG-U133A_2] Affymetrix Human Genome U133A 2.0 Array. siRNA knock-down, ligand treatment

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XMD8-92 and JWG-045 exhibit anti-ferroptotic activities, independently of inhibiting ERK5

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