Mast cell tryptase stimulates DLD-1 carcinoma through prostaglandin-and MAP kinase-dependent manners

Masanori Yoshii, Atsushi Jikuhara, Shuji Mori, Hiromi Iwagaki, Hideo K. Takahashi, Masahiro Nishibori, Noriaki Tanaka

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

We found that striptease-positive mast cells were abundant in the invasive front of human colon adenocarcinoma by examining 30 cases. Because tryptase has been suggested to be the agonist proteinase for protease-activated receptor-2 (PAR-2), we investigated the effects of stimulation of PAR-2 by tryptase on the cell signaling and proliferation of DLD-1, a human colon carcinoma cell line. PAR-2 stimulation by tryptase induced the increase in [Ca2+] i, which was desensitized by the prior application of PAR-2 activating peptide (AP). The proliferative responses of DLD-1 to tryptase and PAR-2 AP were associated with the phosphorylation of MEK and MAP kinase. Inhibition of MEK by PD98059 completely inhibited the proliferationenhancing effects of tryptase and PAR-2 AP as well as phosphorylation of MAP kinase. Moreover, tryptase and PAR-2 AP stimulated the production of prostaglandin E2 and the inhibition of prostaglandin synthesis by indomethacin or NS398 resulted in the complete inhibition of the proliferative responses to tryptase and PAR-2 AP. Furthermore, the tryptase-stimulated proliferation of DLD-1 was concentration-dependently inhibited by nafamostat mesilate, a specific inhibitor of tryptase. These results as a whole indicated that tryptase has proliferative effects on DLD-1 through cyclooxygenase- and MAP kinase-dependent manners acting on PAR-2 by its proteolytic activity.

Original languageEnglish
Pages (from-to)450-458
Number of pages9
JournalJournal of Pharmacological Sciences
Volume98
Issue number4
DOIs
Publication statusPublished - 2005

Keywords

  • Colon cancer
  • MAP kinase
  • MEK
  • Protease-activated receptor-2
  • Tryptase

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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