Expression of serotonin receptors and role of serotonin in human prostate cancer tissue and cell lines.
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.


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.
Dizeyi
N
N
Department of Urology, Malmö University Hospital, Lund University, Sweden. Nishtman.dizeyi@urokir.lu.se
Bjartell
A
A
Nilsson
E
E
Hansson
J
J
Gadaleanu
V
V
Cross
N
N
Abrahamsson
P-A
PA
D015153:Blotting, Western; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009367:Neoplasm Staging; D011471:Prostatic Neoplasms / Q000473:pathology*; D012333:RNA, Messenger / Q000032:analysis; D011985:Receptors, Serotonin / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012701:Serotonin / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology
D012333:RNA, Messenger; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D012701:Serotonin