Fig. 2: Molecular mechanisms underlying MAPK hyperactivation in MPM. | Cell Death Discovery

Fig. 2: Molecular mechanisms underlying MAPK hyperactivation in MPM.

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

Fig. 2

A Schematic of the RAS-RAF-MEK-ERK and the mTOR pathway downstream of RTK signaling. B Gene set variation analysis (GSVA) shows deregulation of the Hallmark modules in MPM tumors compared with normal pleural tissue. The transcriptomic data of MPM samples (GSE2549 dataset) were downloaded from the Gene Expression Omnibus (GEO). Note that the KRAS_signaling_UP signature is significantly enriched in MPM tumors vs. normal pleural tissue. C The RTK pathway proteins (p-IGF1R, p-CMET, HEREGULIN) and the MAPK pathway proteins (p-CRAF, p-MAPK/p-ERK) correlate strongly and positively with p-MEK1 (Ser217/221) in MPM. The numbers in the correlogram indicate the correlation coefficient (Spearman), with significant (P < 0.05) positive and negative correlations shown in blue and red, respectively. The color intensity is proportional to the correlation coefficient, with a non-significant (P > 0.05) correlation in the blank background. D Viability assay of the indicated MPM cells transfected (72 h) with FGFR1-specific or control siRNAs. *p < 0.05, **p < 0.01, ***p < 0.001 by Welch’s t-test (n = 3). E Immunoblots of H2452 cells treated for 12 h with the B/C-RAF inhibitor sorafenib. Note that 2.5 µM sorafenib effectively blocked MEK signaling (decrease in p-MEK). F Viability assay of the indicated MPM cells treated for 96 h with clinically relevant doses (maximal plasma concentration in patients) of the indicated inhibitors. Data are shown as mean ± s.d. (n = 3). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 by Welch’s t-test.

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