c-MYC Protein Stability Is Sustained by MAPKs in Colorectal Cancer

c-MYC is one of the most important factors involved in colorectal cancer (CRC) initiation and progression; indeed, it is found to be upregulated in up to 80% of sporadic cases. During colorectal carcinogenesis, c-MYC is maintained upregulated through beta-catenin-mediated transcriptional activation and ERK-mediated post-translational stabilization. Our data demonstrate that p38 alpha, a kinase involved in CRC metabolism and survival, contributes to c-Myc protein stability. Moreover, we show that p38 alpha, like ERK, stabilizes c-MYC protein levels by preventing its ubiquitination. Of note, we found that p38 alpha phosphorylates c-MYC and interacts with it both in vitro and in cellulo. Extensive molecular analyses in the cellular and in vivo models revealed that the p38 alpha kinase inhibitors, SB202190 and ralimetinib, affect c-MYC protein levels. Ralimetinib also exhibited a synthetic lethality effect when used in combination with the MEK1 inhibitor trametinib. Overall, our findings identify p38 alpha as a promising therapeutic target, acting directly on c-MYC, with potential implications for countering c-MYC-mediated CRC proliferation, metastatic dissemination, and chemoresistance.

Automated summary

c-MYC is a crucial factor in the development of colorectal cancer, with high expression in most sporadic cases. In this study, researchers discovered that the kinase p38 alpha contributes to the stability of c-MYC protein, which is involved in CRC metabolism and survival. Furthermore, p38 alpha prevents ubiquitination of c-MYC, leading to increased levels of the protein. These findings suggest that p38 alpha could be a potential therapeutic target for countering CRC proliferation, metastasis, and chemoresistance mediated by c-MYC.