c-MYC Protein Stability Is Sustained by MAPKs in Colorectal Cancer
c-MYC is a key driver in the initiation and progression of colorectal cancer (CRC), with upregulation observed in up to 80% of sporadic cases. During colorectal carcinogenesis, c-MYC expression is sustained through β-catenin-driven transcriptional activation and ERK-mediated post-translational stabilization. Our data reveal that p38α, a kinase involved in CRC metabolism and cell survival, also plays a crucial role in maintaining c-MYC protein stability. Similar to ERK, p38α prevents c-MYC ubiquitination, thereby stabilizing its protein levels. Importantly, we demonstrate that p38α phosphorylates c-MYC and physically interacts with it both in vitro and in living cells. Comprehensive molecular studies using cellular and in vivo models show that p38α inhibitors, SB202190 and ralimetinib, reduce c-MYC protein levels. Notably, ralimetinib displays a synthetic lethality effect when combined with the MEK1 inhibitor trametinib. Taken together, these findings highlight p38α as a promising therapeutic target that directly regulates c-MYC, offering potential strategies to combat c-MYC-driven CRC proliferation, metastasis, and resistance to chemotherapy.