Expression of Serotonin Receptors and Role of Serotonin in Human Prostate Cancer Tissue and Cell Lines

Prostate. 2004 May 15;59(3):328-36. doi: 10.1002/pros.10374.

Abstract

Background: Increase in the number of serotonin (5-HT) releasing neuroendocrine (NE) cells has been shown to be correlated with tumor progression, loss of androgen dependence, and poor prognosis. Serotonin is a well-known mitogen which mediates a wide variety of physiological effects via multiple receptors, of which receptor subtype 1 (5-HTR1) has been identified in prostate cancer (PC) cell lines. Recently, 5-HT has been found to show growth-promoting activity and to be functionally related to oncogenes.

Materials and methods: Localization, protein content, and mRNA expression of 5-HTR subtype 1A, 1B, and 1D was studied in prostatic tissue (35 patients), metastases, PC cell lines, a benign prostatic stromal cell line (human prostate cell preparation (hPCP)), and xenografts of PC-3 cells by immunohistochemistry (IHC), Western blotting, and RT-PCR, respectively. The growth-inhibition effect of a 5-HT1A antagonist (NAN-190) on PC cell lines was studied using a bromodeoxyuridine (BrdU) assay.

Results: A strong immunoreaction of 5-HTR1A and 1B was demonstrated in high-grade tumor cells (35/35) and a small number of BPH cells, whereas 5-HTR1D was confined to vascular endothelial cells. 5-HTR1A was also demonstrated in PC cells metastasized to lymph node and bone, PC-3, DU145, LNCaP, and in xenografts of PC-3 cells and hPCP. Western blot analysis gave strong bands from PC tissue extracts compared to BPH tissue. Using RT-PCR, 5-HTR1A mRNA was demonstrated in all PC cell lines. An antagonist of 5-HTR1A (NAN-190) inhibited the growth of PC-3, DU145, and LNCaP cells but not of hPCP cells.

Conclusions: This is the first study demonstrating an overexpression of 5-HTR subtypes 1A and 1B in PC cells, especially in high-grade tumors. Moreover, 5-HT stimulates proliferation of PC cells and 5-HTR1A antagonists inhibit proliferation. Thus, we propose that 5-HT has an important role in tumor progression, especially in the androgen-independent state of the disease. The design of specific antagonists for this type of receptor might be useful for the growth control of androgen-independent tumors.

MeSH terms

  • Blotting, Western
  • Disease Progression
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunohistochemistry
  • Male
  • Neoplasm Staging
  • Prostatic Neoplasms / pathology*
  • RNA, Messenger / analysis
  • Receptors, Serotonin / biosynthesis*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serotonin / pharmacology*
  • Serotonin Antagonists / pharmacology

Substances

  • RNA, Messenger
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Serotonin