Fig. 3: MEK inhibition impairs HR and evokes protective PARP in MPM cells. | Cell Death Discovery

Fig. 3: MEK inhibition impairs HR and evokes protective PARP in MPM cells.

From: MEK1 drives oncogenic signaling and interacts with PARP1 for genomic and metabolic homeostasis in malignant pleural mesothelioma

Fig. 3

A Proteins and phosphoproteins whose expression is significantly correlated with p-MEK1 (Ser217/221) protein level in MPM. The green dots indicate the proteins significantly (p < 0.05) negatively correlated with p-MEK1, and the red significantly positively correlated with p-MEK1. The proteins with a correlation threshold (Spearman’s correlation coefficient >0.4 or <−0.4) are marked. RPPA proteomic data of MPM patients were downloaded from TCPA. B Gene set enrichment analysis (GSEA) revealed significant downregulation of homologous recombination (HR) gene signature in ERK1/2-depleted MPM cells. The GSE21750 dataset from the Gene Expression Omnibus (GEO) portal was used for the analysis, with pre-defined HR gene signatures based on Peng et al. (2014) and Severson et al. (2017). C Kaplan–Meier univariate survival analyses of MPM patients (n = 87). Algorithm-based HR signatures are based on the indicated studies. MPM patients are stratified by the optimal cutoff value of the HR score across all patients using the surv_cutpoint function in the R ‘maxstat’ package. The p-value is calculated by the log-rank test. D PARP1 protein level predicts MEKi sensitivity. The blue dots are inhibitors whose IC50 values are significantly (p < 0.05) positively correlated with PARP1 levels, and the red ones are significantly (p < 0.05) negatively correlated with PARP1. The correlation analysis was based on the drug sensitivity profile of thoracic cancer cells (n = 32, including 3 MPM cell lines and 29 lung cancer cell lines) in GDSC. E Immunoblots of MESO-1 and BE261T cells treated with MEKi (trametinib; 0.5 μM) for the indicated time (MESO1) or for 24 h with different concentrations (BE261T). Protein quantification was shown above the protein bands. F Immunoblots of MESO-1 cells treated with trametinib (MEKi; 0.5 µM) and olaparib (PARPi; 5 µM), alone and in combination for the indicated time. G Immunoblots of BE261T and MESO-1 cells treated with olaparib (PARPi) for the indicated time. Protein quantification was shown above the bands.

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