Prolyl oligopeptidase inhibition-induced growth arrest of human gastric cancer cells

Biochem Biophys Res Commun. 2014 Jan 3;443(1):91-6. doi: 10.1016/j.bbrc.2013.11.051. Epub 2013 Nov 20.


Prolyl oligopeptidase (POP) is a serine endopeptidase that hydrolyzes post-proline peptide bonds in peptides that are <30 amino acids in length. We recently reported that POP inhibition suppressed the growth of human neuroblastoma cells. The growth suppression was associated with pronounced G0/G1 cell cycle arrest and increased levels of the CDK inhibitor p27(kip1) and the tumor suppressor p53. In this study, we investigated the mechanism of POP inhibition-induced cell growth arrest using a human gastric cancer cell line, KATO III cells, which had a p53 gene deletion. POP specific inhibitors, 3-({4-[2-(E)-styrylphenoxy]butanoyl}-l-4-hydroxyprolyl)-thiazolidine (SUAM-14746) and benzyloxycarbonyl-thioprolyl-thioprolinal, or RNAi-mediated POP knockdown inhibited the growth of KATO III cells irrespective of their p53 status. SUAM-14746-induced growth inhibition was associated with G0/G1 cell cycle phase arrest and increased levels of p27(kip1) in the nuclei and the pRb2/p130 protein expression. Moreover, SUAM-14746-mediated cell cycle arrest of KATO III cells was associated with an increase in the quiescent G0 state, defined by low level staining for the proliferation marker, Ki-67. These results indicate that POP may be a positive regulator of cell cycle progression by regulating the exit from and/or reentry into the cell cycle by KATO III cells.

Keywords: Cell cycle arrest; Human gastric cancer cells; Prolyl oligopeptidase; Quiescent G(0) state; SUAM-14746.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Checkpoints* / drug effects
  • Cell Cycle Checkpoints* / genetics
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Gene Deletion
  • Gene Knockdown Techniques
  • Humans
  • Proline / analogs & derivatives
  • Proline / pharmacology
  • Prolyl Oligopeptidases
  • RNA Interference
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism*
  • Stomach Neoplasms / enzymology*
  • Stomach Neoplasms / pathology*
  • Thiazolidines / pharmacology


  • 3-((4-(2-styrylphenoxy)butanoyl)-4-hydroxyprolyl)thiazolidine
  • Thiazolidines
  • Cyclin-Dependent Kinase Inhibitor p27
  • Proline
  • Serine Endopeptidases
  • PREPL protein, human
  • Prolyl Oligopeptidases