# Involvement of the Orexinergic System in Cancer: Antitumor Strategies and Future Perspectives
## 3 Orexins and Cancer
### Prostate Cancer  
The expression of OXRs has been detected in patients with prostate cancer (90%), with benign prostate hyperplasia (53.3%), or with chronic prostatitis (26.7%) [122]. Only five patients belonging to the first group showed a strong staining, whereas the rest of the patients showed a weak immunoreactivity. In addition, the distribution of OXRs was more widespread in patients with prostate cancer than that found in those with benign prostate hyperplasia or with chronic prostatitis [122]. The authors suggest that OXR expression can be an indicator of poor prognosis in prostate cancer. No expression of OXR/prepro-orexin genes has been reported in human normal (PrSmC, PrSc, PrEC) and prostate cancer (PC3, LNCaP, Du145) cells [123]. However, the presence of OXR1 and prepro-orexin has been described in human normal and hyperplastic prostate tissues, as well as the expression of orexin A, OXR1, and prepro-orexin in human prostate cancer tissues [124]. Moreover, orexin A upregulated the expression of OXR1 and decreased the survival of human LNCaP cells (androgen-dependent prostate carcinoma cells) [124]. The peptide also prevented the testosterone-induced nuclear translocation of the androgen receptor in LNCaP cells; this was counteracted with SB-408,124, an OXR1 antagonist. This is important since orexin A, via OXR1, interferes with the activity of the androgen receptor which controls prostate cancer onset and progression [124].  
OXR2 mRNA/protein expressions, but not OXR1/prepro-orexin, have been observed in normal prostate glands (apical region of epithelial cells, smooth muscle cells) and benign prostatic hyperplasia [57]. An OXR2 upregulation associated with a low serum orexin A level was found in benign prostatic hyperplasia; the serum orexin A level was not changed in prostate cancer compared to control samples, whereas the level of orexin B was similar in all groups studied [57]. The results suggest that orexin A/OXR2 are involved in the maintenance and/or pathogenesis of benign prostatic hyperplasia.  
OXR1 mediated apoptosis, and it has been reported that this receptor was overexpressed in advanced prostate cancer, but its expression was lower in low-grade prostate tumors [125]. The number of cells expressing this receptor augmented according to the prostate cancer grade, whereas OXR2 was observed in a few malignant cells in high-grade prostate cancer [125]. Moreover, orexin A was not observed in normal prostate epithelium and, in addition, the peptide was not observed in tumor tissues [125; 126]. Thus, it seems that normal/cancer cells located inside and surrounding the tumor do not express orexin A. OXR1 was found in androgen-dependent LNCaP cells and in androgen-independent Du145 cells; the acquisition of a neuroendocrine phenotype by the latter cells has been related to OXR1 overexpression [125]. Both orexins increased non-transformed Du145 cell growth but, when these cells suffered neuroendocrine transformation, apoptosis was observed when they were treated with orexin A [125]. Thus, it seems that orexin could exert a beneficial action against prostate cancer at a certain period. Orexin A, via OXR1, blocked cell growth in LNCaP and Du145 cells, and the peptide decreased the tumor volume of xenografted Du145 cells [124; 125; 126; 127].