Suarez-Lopez, L. | bioRxiv Science

bioRxiv2026

MAPKAP Kinase-2 signaling enhances the resolution of colonic inflammation through specialized pro-resolving mediators

Failure to resolve acute inflammation contributes to chronic inflammatory diseases, including inflammatory bowel disease, and inflammation associated cancer. MAPKAP kinase-2 (MK2), a stress-activated effector of p38MAPK, is best known for promoting onset and amplification of inflammation through post-transcriptional regulation of cytokines. Here we identify an unexpected role for MK2 in coordinating resolution of intestinal inflammation. Following dextran sodium sulfate induced colonic injury, MK2 deficient mice developed more severe, persistent inflammation, with sustained proinflammatory cytokine and chemokine production, prolonged neutrophil accumulation, and impaired macrophage recruitment during recovery. Myeloid-restricted MK2 deficiency recapitulated the impaired resolution phenotype. Lipid mediator metabololipidomics revealed MK2 deficient colons failed to undergo the transition from pro-inflammatory to pro-resolving lipid mediator production, exhibiting markedly reduced levels of specialized pro-resolving mediators (SPMs), including resolvins and lipoxins. Exogenous SPM administration during the recovery phase restored inflammation resolution in MK2 deficient mice, improving weight, disease activity, and mucosal healing. These findings establish a previously unrecognized role for MK2 in coordinating the transition from inflammatory injury to resolution and repair. Together with our prior finding that myeloid MK2 deficiency reduces colitis-associated tumor progression, these results suggest that inflammation associated tumorigenesis depends not simply on inflammatory injury, but on its coupling to the resolution and tissue repair that follows.

systems biology↗

bioRxiv2023

An RNA Damage Response Network Mediates the Lethality of 5-FU in Clinically Relevant Tumor Types

5-fluorouracil (5-FU) is a successful and broadly used anti-cancer therapeutic. A major mechanism of action of 5-FU is thought to be through thymidylate synthase (TYMS) inhibition resulting in dTTP depletion and activation of the DNA damage response. This suggests that 5-FU should synergize with other DNA damaging agents. However, we found that combinations of 5-FU and oxaliplatin or irinotecan failed to display any evidence of synergy in clinical trials, and resulted in sub-additive killing in a panel of colorectal cancer (CRC) cell lines. In seeking to understand this antagonism, we unexpectedly found that an RNA damage response during ribosome biogenesis dominates the drugs efficacy in tumor types for which 5-FU shows clinical benefit. 5-FU has an inherent bias for RNA incorporation, and blocking this greatly reduced drug-induced lethality, indicating that accumulation of damaged RNA is more deleterious than the lack of new RNA synthesis. Using 5-FU metabolites that specifically incorporate into either RNA or DNA revealed that CRC cell lines and patient-derived colorectal cancer organoids are inherently more sensitive to RNA damage. This difference held true in cell lines from other tissues in which 5-FU has shown clinical utility, whereas cell lines from tumor tissues that lack clinical 5-FU responsiveness typically showed greater sensitivity to the drugs DNA damage effects. Analysis of changes in the phosphoproteome and ubiquitinome shows RNA damage triggers the selective ubiquitination of multiple ribosomal proteins leading to autophagy-dependent rRNA catabolism and proteasome-dependent degradation of ubiquitinated ribosome proteins. Further, RNA damage response to 5-FU is selectively enhanced by compounds that promote ribosome biogenesis, such as KDM2A inhibitors. These results demonstrate the presence of a strong RNA damage response linked to apoptotic cell death, with clear utility of combinatorially targeting this response in cancer therapy.

cancer biology↗