MAP kinase-mediated proliferation of DLD-1 carcinoma by the stimulation of protease-activated receptor 2

Atsushi Jikuhara, Masanori Yoshii, Hiromi Iwagaki, Shuji Mori, Masahiro Nishibori, Noriaki Tanaka

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)


Protease-activated receptor-2 (PAR-2) has been demonstrated to be highly expressed in the gastrointestinal tract. In the present study, we investigated the effects of PAR-2 stimulation on the cell signaling and proliferation of DLD-1, a human colon carcinoma cell line, in comparison with the PAR-1 stimulation. PAR-2 stimulation by agonist peptide SLIGKV concentration-dependently induced the increase in [Ca2+]i and the proliferation of DLD-1 whereas the inverse peptide LSIGKV did not. Trypin (10-9 M), an agonist protease for PAR-2, also enhanced the proliferation of DLD-1. The proliferative response of DLD-1 to PAR-2 stimulation was associated with the transient phosphorylation of MEK and MAP kinase, but not p38 MAP kinase and JNK. Inhibition of MEK by PD98059 (50 μM) completely inhibited the proliferation-stimulating effects as well as the phosphorylation of MAP kinase induced by PAR-2 agonist peptide (100 μM) and trypsin (10-9 M). The prolonged treatment with PAR-2 agonist peptide for more than one hour was required for the enhanced proliferative response, suggesting the existence of unknown long-lasting cooperative signaling with MAP kinase cascade. PAR-1 stimulation by the agonist peptide SFLLRN (100 μM) or thrombin (10-8 M) produced Ca2+ signaling, however, the stimulation neither produced the cell proliferative response nor the activation of MEK-MAP kinase cascade. These results indicated that Ca2+ signaling induced by PARs activation was not enough for inducing the cell proliferation in DLD-1 cells and that stimulation of PAR-2 can induce the activation of MEK-MAP kinase cascade, leading to the growth promoting response.

Original languageEnglish
Pages (from-to)2817-2829
Number of pages13
JournalLife Sciences
Issue number22
Publication statusPublished - Oct 17 2003


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

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology
  • Pharmacology, Toxicology and Pharmaceutics(all)


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