Characterization of Dopamine Receptor Associated Drugs on the Proliferation and Apoptosis of Prostate Cancer Cell Lines.

BACKGROUND: Dopamine Receptor (DR) gene family play an essential role in the regulation of Interleukin- 6 (IL-6) production. Our prior analysis of human prostate biopsy samples demonstrated the increased expression of IL-6 and a downregulating trend for dopamine receptor gene family. OBJECTIVE: The objective was to investigate the expression of dopamine receptors, their catabolizing enzyme and IL-6 in prostate cancer cell lines and assess pharmacological effect of dopamine receptor modulators as a novel class of drugs repurposed for the treatment of prostate cancer. METHODS: The therapeutic effect of dopamine, DR agonists, and DR antagonist were examined using LNCaP and PC3 cell lines. Cell viability and proliferation were assessed by MTT assay and proliferating cell nuclear antigen expression analysis, respectively. Furthermore, bax/bcl2 ratio, immunofluorescence assay and flow cytometric assay were performed for apoptosis analysis. RT- qPCR analysis was used to characterize the relative expression of dopamine-related genes, catabolic enzyme Catechol-o-Methyl-Transferase (COMT) and IL-6 before and after treatment to assess the therapeutic effects of drugs. RESULTS: LNCaP cells express DRD1, DRD2, DRD5 and COMT genes and PC3 cells only express IL-6 gene. In-vitro, dopamine receptor agonists reduced cell viability of LNCaP and PC3 cells. In contrast, dopamine and dopamine receptor antagonist significantly increased tumor growth in PC3 cells. CONCLUSION: Our results offer novel suggestion for a pathogenic role of dopamine receptor signaling in prostate cancer adenocarcinoma and indicates that modulators of DR- IL-6 pathway, including FDA-approved drug bromocriptine, might be utilized as novel drug repurposing strategy.

Novel Insight into Differential Gene Expression and Clinical Significance of Dopamine Receptors, COMT, and IL6 in BPH and Prostate Cancer.

BACKGROUND: Benign prostatic hyperplasia (BPH) and prostate cancer (PCa) are the most prevalent diseases in male population, implicated with fundamental differences between benign and malignant growth of prostate cells. An imbalance through a network of nervous, endocrine, and immune systems initiate a signal of altered growth from the brain to the prostate gland, leading to adverse effects such as inflammation. OBJECTIVE: The aim of this study was to evaluate the gene expression of dopamine receptor family, COMT, and IL6 to identify novel correlations in BPH and PCa in both blood and tumor of the patients. METHODS: Peripheral blood mononuclear cells from BPH (n= 30) and PCa (n= 30) patients, and prostate tumor tissues (n= 14) along with pathologically normal adjacent tissues (n= 14) were isolated, mRNA was extracted, and cDNA was synthesized, respectively. Quantitative real- time PCR was applied for DRD1- DRD5, COMT, and IL6 genes in all samples. RESULTS: We found, for the first time, that the expression of COMT and IL6 genes were inversely correlated with the expression of DRD1 and DRD2 genes through the extent of differentiation of PCa from BPH condition. In addition, the PSA levels were correlated with the expression of DRD1 in BPH cases and DRD1, DRD4, DRD5, and IL6 in PCa cases. CONCLUSION: Results implicate a potential cross- talk between the signaling pathways derived by IL6 cytokine and dopamine receptors in PCa. Thus, it seems promising to reassemble the consequent signaling pathways by adequate agonists and antagonists to help increase therapeutic efficacy.

E1A oncogene expression inhibits PTHrP P3 promoter activity and sensitizes human prostate cancer cells to TNF-induced apoptosis.

In the advanced stages of prostate cancer, tumor cells can evolve to become androgen-independent and resistant to injury-induced apoptosis. Tumor cell expression of parathyroid hormone-related protein (PTHrP) may contribute to the apoptosis phenotype. Expression of the adenovirus E1A oncogene repressed PTHrP promoter and mRNA expression in human PC-3 prostate cancer cells and increased the caspase 3 activation and sensitivity of these cells to apoptosis triggered by tumor necrosis factor alpha. These results suggest that strategies aimed at modulating PTHrP expression may increase the efficacy of innate immune effector mechanisms and proapoptotic, therapeutics in prostate cancer.

Parathyroid hormone-related protein in prostate cancer.

Although originally discovered as the peptide responsible for humoral hypercalcemia of malignancy (HHM), parathyroid hormone-related protein (PTHrP) has been shown to play a major role in fetal development. In the adult, it is widely distributed in normal and various cancer tissues. In spite of the rarity of HHM in prostate cancer, PTHrP is widely distributed in prostate cancer cells. PTHrP is a precursor molecule with generation of various fragments with distinct biological activities. More recent studies have shown that there is intranuclear localization of PTHrP and that intracrine effects of the peptide are involved in promoting processes that result in tumor progression (nall proliferation, apoptosis, cell attachment and angiogenesis) in prostate cancer. PTHrP expression is controlled by three distinct promoters, with P3 being used most often in cancer cells. The factors that control PTHrP production via interaction with the promoters are growth factors, androgens, vitamin D analogs, and adenoviral proteins. TGF-beta and its effector Smad3 activate the P3 promoter through an AGAC box and an Ets binding site involving Ets1 and to some extent Ets2 proteins. In addition, TGF-beta stimulates P3 promoter activity via Smad-independent pathways that involve the p38 MAP kinase. Although the addition of PTHrP or transfection with the PTHrP gene in prostate cells results in effects that promote tumor development, studies that employ inhibition of PTHrP activity in vitro and in vivo are needed to establish a definitive role of this peptide in the pathogenesis of prostate cancer.