ABSTRACT
AIM: In the present study, we have examined the presence of orexins and their receptors in prostate cancer (CaP) and investigated their effects on the apoptosis of prostate cancer cells. METHODS: We have localised the orexin type 1 and 2 receptors (OX1R and OX2R) and orexin A (OxA) in CaP sections of various grades and we have quantified tumour cells containing OX1R. Expression of OX1R was evaluated in the androgeno-dependent (AD) LNCaP and the androgeno-independent (AI) DU145 prostate cancer cells submitted or not to a neuroendocrine differentiation. The effects of orexins on the apoptosis and viability of DU145 cells were also investigated. RESULTS: OX1R is strongly expressed in carcinomatous foci exhibiting a neuroendocrine differentiation, and the number of OX1R-stained cancer cells increases with the grade of the CaP. In contrast, OX2R is only detected in scattered malignant cells in high grade CaP. OX1R is expressed in the AI DU145 cells but is undetectable in the LNCaP cells. Acquisition of a neuroendocrine phenotype by the DU145 cells is associated with an overexpression of OX1R. Orexins induce the apoptosis of DU145 cells submitted to a neuroendocrine differentiation. CONCLUSION: The present data indicate that OX1R-driven apoptosis is overexpressed in AI CaP exhibiting a neuroendocrine differentiation opening a gate for novel therapies for these aggressive cancers which are incurable until now.
Subject(s)
Neuroendocrine Cells , Orexin Receptors/physiology , Prostatic Neoplasms/metabolism , Apoptosis/physiology , Cell Proliferation , Cell Survival/physiology , Humans , Immunohistochemistry , Male , Neuroendocrine Cells/metabolism , Neuroendocrine Cells/pathology , Orexin Receptors/genetics , Prostatic Neoplasms/pathology , RNA, Messenger/metabolism , Tumor Cells, CulturedABSTRACT
AIM: Accumulating data suggest that neuropeptides produced by neuroendocrine cells play a crucial role in the progression and aggressiveness of hormone refractory prostate cancer (CaP). In this study, we have investigated the presence and function of the neuropeptide 26RFa in CaP. METHODS: We have localised and quantified tumour cells containing 26RFa and its receptor, GPR103, in CaP sections of various grades. In vitro experiments were performed to investigate the effects of 26RFa on the migration, proliferation and neuroendocrine differentiation of the androgeno-independent (AI) prostate cancer cell line DU145. RESULTS: 26RFa and GPR103 are present in carcinomatous foci exhibiting a neuroendocrine differentiation, and the number of 26RFa and GPR103-immunoreactive cancer cells increases with the grade of CaP. 26RFa stimulated the migration of native or transdifferentiated AI DU145 cells, but had no effect on their proliferation. Furthermore, 26RFa induced the neuroendocrine differentiation of DU145 cells as assessed by the occurrence of neurite-like extensions and the increase of the expression of the neuroendocrine marker chromogranin A. CONCLUSION: The present data indicate that 26RFa may participate to the development of CaP at the AI state by promoting the neuroendocrine differentiation and the migration of cancer cells via autocrine/paracrine mechanisms.
