Endothelin-1 production and agonist activities in cultured prostate-derived cells: implications for regulation of endothelin bioactivity and bioavailability in prostatic hyperplasia

Prostate. 1998 Mar 1;34(4):241-50. doi: 10.1002/(sici)1097-0045(19980301)34:4<241::aid-pros1>3.0.co;2-k.

Abstract

Background: Endothelin-1 (ET-1) interacts with specific G-protein-coupled receptors to initiate short-term (contraction) and long-term (mitogenesis) events in target cells. ET-1 is an abundant prostate secretory protein that, in its biologically active form, elicits prostatic smooth muscle contraction. The present study was designed to determine the effects of ET-1 on prostate cell growth and to examine the regulation of endogenous ET-1 activity and bioavailability.

Methods: Primary cultures of prostate secretory epithelial (PE) and prostate fibromuscular stromal (PS) cells were established from benign human prostate tissue.

Results: In culture, PE cells secrete immunoreactive ET-1 (38.5 +/- 1.6 pg/ml/10(6) cells/24 hr) into the conditioned medium. Levels of immunoreactive ET-1 produced by PS cells were more than 10-fold lower. Endothelin-converting enzyme-1 (ECE-1) mRNA was detected in PE cells and not in PS cells; however, big ET-1 was the predominant immunoreactive ET-1 secretory product of PE cells. The ET(B) endothelin receptor was the predominant subtype in both PE and PS cells. In PS cells, but not PE cells, ET-1 induced significant inositol phosphate accumulation and [3H]-thymidine uptake. Agonist activity was inhibited by the ET(B) receptor selective antagonist, BQ 788. Intact PE cell monolayers secrete ET-1 through the apical surface, consistent with secretion of ET-1 into the glandular lumen in vivo.

Conclusions: On the basis of these findings, regulation of ET-1 activity and bioavailability appears to be tightly regulated. Such findings have important implications in the pathophysiology of prostate disease.

MeSH terms

  • Apoptosis
  • Aspartic Acid Endopeptidases / biosynthesis
  • Aspartic Acid Endopeptidases / genetics
  • Biological Availability
  • Endothelin-1 / biosynthesis
  • Endothelin-1 / metabolism*
  • Endothelin-1 / pharmacokinetics
  • Endothelin-3 / analysis
  • Endothelin-Converting Enzymes
  • Humans
  • Male
  • Metalloendopeptidases
  • Prostate / cytology
  • Prostate / metabolism*
  • Prostatic Hyperplasia / metabolism*
  • Receptor, Endothelin A
  • Receptor, Endothelin B
  • Receptors, Endothelin / biosynthesis
  • Receptors, Endothelin / genetics
  • Tumor Cells, Cultured

Substances

  • Endothelin-1
  • Endothelin-3
  • Receptor, Endothelin A
  • Receptor, Endothelin B
  • Receptors, Endothelin
  • Aspartic Acid Endopeptidases
  • Metalloendopeptidases
  • ECE1 protein, human
  • Endothelin-Converting Enzymes