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

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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.