| Autor: |
Lepore Signorile, Martina, Fasano, Candida, Forte, Giovanna, De Marco, Katia, Sanese, Paola, Disciglio, Vittoria, Di Nicola, Elisabetta, Pantaleo, Antonino, Simone, Cristiano, Grossi, Valentina |
| Předmět: |
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| Zdroj: |
Cell & Bioscience; 12/1/2023, Vol. 13 Issue 1, p1-20, 20p |
| Abstrakt: |
Background: Activation of the Wnt pathway has been linked to colorectal cancer (CRC). Previous reports suggest that Wnt3a can activate p38. Besides, p38α feeds into the canonical Wnt/β-catenin pathway by inhibiting GSK3β through phosphorylation. Recently, we identified p38α as a new druggable member of β-catenin chromatin-associated kinase complexes in CRC. Methods: The functional relationship between p38α and β-catenin was characterized in CRC cells, patient-derived CRC stem cells, patient-derived tumor intestinal organoids, and in vivo models (C57BL/6-APCMin/+ mice). The role of p38α in β-catenin transcriptional activity was assessed by pharmacological inhibition with ralimetinib. Results: We used the GSK3β inhibitor TWS-119, which promotes the activation of Wnt signaling, to uncouple p38α nuclear/cytoplasmatic functions in the Wnt pathway. Upon GSK3β inhibition, nuclear p38α phosphorylates β-catenin at residues S111 and T112, allowing its binding to promoter regions of Wnt target genes and the activation of a transcriptional program implicated in cancer progression. If p38α is pharmacologically inhibited in addition to GSK3β, β-catenin is prevented from promoting target gene transcription, which is expected to impair carcinogenesis. Conclusions: p38α seems to play a dual role as a member of the β-catenin destruction complex and as a β-catenin chromatin-associated kinase in CRC. This finding may help elucidate mechanisms contributing to human colon tumor pathogenesis and devise new strategies for personalized CRC treatment. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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