| Abstract |
Prostate cancer is second, only to lung cancer, most common cause of death from cancer in men. The incidence of prostate cancer increases rapidly with age. A large number of different factors (genetic and environmental) are involved in initiation and progression of prostate cancer but their role remains uncertain. In addition, the presence of foci of cancer within the prostate gland is much more common than the clinically diagnosed disease. Possibly a number of different factors interact locally within the prostate gland and promote or inhibit tumor growth, including neuropeptides and specifically opioids which can reach prostate either through the general circulation (β-endorphine and food derived peptides) or being locally produced by neuroendocrine cells present in the prostate gland. The results of the present study provide evidences for a possible involvement of opioids in the prostate cancer. It was found that opioids, alkaloids, peptides and casomorphines, inhibit cell growth of three human prostate cancer cell lines (DU-145, PC3 and LNCaP). Their inhibitory action on DU-145 and PC3 cells can be reversed by the general opioid antagonist, diprenorphine, an action indicateng a mediation through specific opioid binding sites. Indeed, opioid receptors were identified in both cell lines: DU-145 cells bear mu, kappa 1 and kappa 3 opioid receptors while in PC3 cells mu and kappa 1 sites were identified. On the contrary, LNCaP cells where the action of opioids was not reversed bur rather enhanced by the opioid antagonist diprenorphine, no opioids receptors were identified. The inhibitory action of casomorphins tested was lower than the action of alkaloids and peptides studied, while the same participation of opioid receptors was identified. The three different prostate cancer cell lines used in our study were selected in order to have different degree of differentiation and represent different stages of prostate cancer. From our results it seems that opioids receptors are present in more advanced, hormone independent, stages of prostate cancer. The fact that opioid action in DU-145 and PC3 cells is not completely reversed by diprenorphine, in combination with the absence of opioid receptors in LNCaP cells indicate that their action might not be mediated only through opioid receptors. Therefore, we first tested the possibility for their action to be mediated via other membrane receptor systems, presenting an homology with opioid receptors and secondly by interacting with other systems. A small number of somatostatin receptors were identified only in DU-145 and PC3 cells but opioids did not bind to them. In LNCaP cells, α1 adrenergic receptors were identified. EKC binds to α1 adrenergic receptors and part of its inhibitory action is mediated through them. Moreover, in the hormone dependent LNCaP cells a rapid non genomic action of androgens was observed inducing PSA secretion. This action was mediated via specific membrane binding sites identified in LNCaP cells. The rapid action of testosterone through membrane binding sites results in reorganization of actin cytoskeleton which is responsible for the increase in PSA secretion. Opioids, specifically EKC, inhibit the rapid androgen induced, PSA secretion, probably by interacting with actin cytoskeleton, while long term androgen action is inhibited by opioids probably by reducing the number of androgen membrane binding sites. Finally, it was found that an alternative way of opioid action could be the system of nitric oxide. Indeed, breast cancer cells produce nitric oxide and opioids inhibit its production by directly interacting with nitric oxide synthase (NOS). Prostate cancer cell lines also produce NO but opioids do not directly affect NOS activity indicating a different mechanism of action. In parallel, studying the action of different opioids, two new opioid peptides were identified: a) αs1 casomorphine which was derived from the sequence of human αs casein and could be released by the action of proteolytic enzymes. It shows a very potent antiproliferative action in prostate and breast cancer cells. Its action is mediated mainly through kappa opioid receptors, binding to them with high affinity and mu opioid receptors. Replacing the carboxylic end of αs1 casomorphine with an amino group resulted in a lower action. b) Receptorphin which also strongly inhibits cell growth via opioid receptors. The significance of this peptide, relies on the fact that its sequence is found on the second transmembrane region of opioid receptors in different species. Possible release of receptorphin after cell death could induce a positive feedback in the action of different factors that cause cell death. In conclusion, the results of the present study supply evidences for a possible role of opioids in the growth of prostate cancer cells, as well as, a new, more physiologic, approach to the treatment of prostate cancer.
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