Abstract
Glutamine RF-amide peptide (QRFP) belongs to the RFamide neuropeptide family, which is involved in a wide spectrum of biological activities, ranging from food intake and cardiovascular functioning to analgesia, aldosterone secretion, locomotor activity and reproduction. Recently, QRFP has been demonstrated to exert its effects by activating the G protein-coupled receptor GPR103. QRFP is expressed in the brain and peripherally in the adipose tissue, bladder, colon, testis, parathyroid and thyroid gland, as well as in the prostate gland. Following lung cancer, prostate cancer constitutes the second most frequently diagnosed cancer among men, whilst obesity appears to be a contributing factor for aggressive prostate cancer. In the present study, we sought to investigate the role of QRFP in prostate cancer, using two androgen-independent human prostate cancer cell lines (PC3 and DU145) as in vitro experimental models and clinical human prostate cancer samples. The expression of both QRFP and GPR103 at the gene and protein level was higher in human prostate cancer tissue samples compared to control and benign prostatic hyperplasia (BHP) samples. Furthermore, in both prostate cancer cell lines used in the present study, QRFP treatment induced the phosphorylation of ERK1/2, p38, JNK and Akt. In addition, QRFP increased cell migration and invasion in these in vitro models, with the increased expression of MMP2. Furthermore, we demonstrated that the pleiotropic adipokine, leptin, increased the expression of QRFP and GPR103 in PC3 prostate cancer cells via a PI3K- and MAPK-dependent mechanism, indicating a novel potential link between adiposity and prostate cancer. Our findings expand the existing evidence and provide novel insight into the implication of QRFP in prostate cancer.
Highlights
RFamide peptides comprise a family of neuropeptides which are characterized by a common carboxy‐terminal motif consisting of an arginine (R) and an amidated phenylalanine (F) [1]
QRFP and G protein‐coupled receptor 103 (GPR103) mRNA levels in human prostate tissue samples were determined by reverse transcription‐quantitative PCR (RT‐quantitative polymerase chain reaction (qPCR)), which revealed that the gene expression of both QRFP and GPR103 was significantly higher in the prostate cancer samples (n=5) compared to the samples from benign prostate hyperplasia patients (BPH; n=5) (Fig. 1A)
We revealed that QRFP and its cognate receptor GPR103 were expressed in two androgen‐independent human prostate cancer cell lines (PC3 and DU145), and that their expression was upregulated in human prostate cancer tissue samples compared to that in samples from benign prostate hyperplasia patients
Summary
RFamide peptides comprise a family of neuropeptides which are characterized by a common carboxy‐terminal motif consisting of an arginine (R) and an amidated phenylalanine (F) [1]. Vertebrate RFamides are categorized into five groups, namely i) the neuropeptide FF (NPFF); ii) the prolactin‐releasing peptide (PrRP); iii) the gonadotropin‐inhibitory hormone (GnIH); iv) the kisspeptin ( known as metastin); and v) the 26RFa/QRFP group [2,3]. The latter was initially identified in frog brain [4], with the N‐extended longest form of the glutamine RF‐amide peptide (QRFP) consisting of 43 amino acids, while due to several processing sites of this peptide a 26 (26RFa), 6 (26RFa20‐26) and 9 (9RFa) amino acid form can be produced [4,5,6,7]. GPR103 shares 48 and 47% protein sequence homology with the two orexin receptors, OX1R and OX2R, respectively [8].
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