title: 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.affiliation: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Dilly
authors.affiliation: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: Herbert J
authors.initials: HJ
authors.lastname: Zeh
authors.affiliation: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: Zong S
authors.initials: ZS
authors.lastname: Guo
authors.affiliation: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA; Department of Pharmacology and Chemical Biology, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: Yong J
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: David L
authors.initials: DL
authors.lastname: Bartlett
authors.affiliation: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA. Electronic address: choudrymh@upmc.edu.
authors.forename: Haroon A
authors.initials: HA
authors.lastname: Choudry
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055262:Mucin-2 / Q000096:biosynthesis* / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000201:enzymology* / Q000473:pathology*; D010534:Peritoneal Neoplasms / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011553:Pseudomyxoma Peritonei / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology; D016019:Survival Analysis; D018808:Transcription Factor AP-1 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C524625:MUC2 protein, human; D055262:Mucin-2; C544830:N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D018808:Transcription Factor AP-1; D004159:Diphenylamine; D020928:Mitogen-Activated Protein Kinases