Aminopeptidase N regulated by zinc in human prostate participates in tumor cell invasion

Int J Cancer. 2001 Apr 1;92(1):49-54.

Abstract

Aminopeptidase N (AP-N) degrades collagen type IV and is proposed to play a role in tumor invasion. However, the precise functions of AP-N in tumor cells and the relationship of AP-N to prostate cancer remains unclear. In our study, we examined a possible role for zinc in the regulation of AP-N enzymatic activity in relation to tumor cell invasion in human prostate. AP-N purified from human prostate was irreversibly inhibited by low concentrations of zinc (Ki = 11.2 microM) and bestatin. AP-N, which has zinc in the active center, was also inhibited by the chelating agents, EDTA, o-phenanthroline and EGTA. EDTA was shown to remove zinc from the enzyme. When the effects of zinc and bestatin on invasion of PC-3 cells were investigated in vitro using a Transwell cell-culture chamber, zinc and bestatin effectively suppressed cell invasion into Matrigel at the concentration range of 50-100 microM. These results strongly suggest that the suppression of PC-3 cell invasion by zinc is based on the inhibition of AP-N activity by zinc. We also evaluated the expression of AP-N to investigate the relationship with the progression of prostate disease in human cancerous prostate. AP-N was found to be located at the cytoplasmic membranes of prostate gland epithelial cells and to be expressed more in prostate cancer, while the expression of prostate-specific antigen (PSA), which is a useful marker for prostate cancer, was shown in normal and cancer tissues, suggesting that AP-N is potentially a good histological marker of prostate cancer. Thus, highly expressed AP-N in human cancerous prostate probably plays an important role in the invasion and metastasis of prostate cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • CD13 Antigens / analysis
  • CD13 Antigens / antagonists & inhibitors
  • CD13 Antigens / metabolism*
  • Copper / pharmacology
  • Dose-Response Relationship, Drug
  • Edetic Acid / pharmacology
  • Egtazic Acid / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Epithelium / enzymology
  • Humans
  • Immunohistochemistry
  • Leucine / analogs & derivatives
  • Leucine / pharmacology
  • Male
  • Neoplasm Invasiveness*
  • Peptide Fragments / chemistry
  • Phenanthrolines / pharmacology
  • Prostate / enzymology*
  • Prostatic Hyperplasia / enzymology
  • Prostatic Neoplasms / enzymology*
  • Prostatic Neoplasms / pathology*
  • Substrate Specificity
  • Tumor Cells, Cultured
  • Zinc / pharmacology*

Substances

  • Enzyme Inhibitors
  • Peptide Fragments
  • Phenanthrolines
  • Egtazic Acid
  • Copper
  • Edetic Acid
  • CD13 Antigens
  • Leucine
  • ubenimex
  • Zinc
  • 1,10-phenanthroline