Mitogen-activated protein kinase inhibition reduces mucin 2 production and mucinous tumor growth

Transl Res. 2015 Oct;166(4):344-54. doi: 10.1016/j.trsl.2015.03.004. Epub 2015 Mar 28.


Excessive accumulation of mucin 2 (MUC2) protein (a gel-forming secreted mucin) within the peritoneal cavity is the major cause of morbidity and mortality in pseudomyxoma peritonei (PMP), a unique mucinous malignancy of the appendix. Mitogen-activated protein kinase (MAPK) signaling pathway is upregulated in PMP and has been shown to modulate MUC2 promoter activity. We hypothesized that targeted inhibition of the MAPK pathway would be a novel, effective, and safe therapeutic strategy to reduce MUC2 production and mucinous tumor growth. We tested RDEA119, a specific MEK1/2 (MAPK extracellular signal-regulated kinase [ERK] kinase) inhibitor, in MUC2-secreting LS174T cells, human PMP explant tissue, and in a unique intraperitoneal murine xenograft model of PMP. RDEA119 reduced ERK1/2 phosphorylation and inhibited MUC2 messenger RNA and protein expression in vitro. In the xenograft model, chronic oral therapy with RDEA119 inhibited mucinous tumor growth in an MAPK pathway-dependent manner and this translated into a significant improvement in survival. RDEA119 downregulated phosphorylated ERK1/2 and nuclear factor κB p65 protein signaling and reduced activating protein 1 (AP1) transcription factor binding to the MUC2 promoter in LS174T cells. This study provides a preclinical rationale for the use of MEK inhibitors to treat patients with PMP.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Diphenylamine / analogs & derivatives
  • Diphenylamine / pharmacology
  • Humans
  • MAP Kinase Signaling System / drug effects
  • Mice, Nude
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinases / metabolism
  • Mucin-2 / biosynthesis*
  • Mucin-2 / genetics
  • NF-kappa B / metabolism
  • Neoplasms, Cystic, Mucinous, and Serous / enzymology*
  • Neoplasms, Cystic, Mucinous, and Serous / pathology*
  • Peritoneal Neoplasms / metabolism
  • Peritoneal Neoplasms / pathology
  • Promoter Regions, Genetic / genetics
  • Protein Kinase Inhibitors / pharmacology
  • Pseudomyxoma Peritonei / metabolism
  • Pseudomyxoma Peritonei / pathology
  • Sulfonamides / pharmacology
  • Survival Analysis
  • Transcription Factor AP-1 / metabolism
  • Xenograft Model Antitumor Assays


  • MUC2 protein, human
  • Mucin-2
  • N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide
  • NF-kappa B
  • Protein Kinase Inhibitors
  • Sulfonamides
  • Transcription Factor AP-1
  • Diphenylamine
  • Mitogen-Activated Protein Kinases