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

Abstract

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.

• Authors: Ashok K Dilly, Xinxin Song, Herbert J Zeh, Zong S Guo, Yong J Lee, David L Bartlett, Haroon A Choudry
• Journal: Translational research : the journal of laboratory and clinical medicine (Transl Res) Vol. 166 Issue 4 Pg. 344-54 (Oct 2015) ISSN: 1878-1810 [Electronic] United States
• PMID: 25890193 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• 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

Topics

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