Expression of vasoactive intestinal peptide and functional VIP receptors in human prostate cancer: antagonistic action of a growth-hormone-releasing hormone analog.
Vasoactive intestinal peptide (VIP) functions as a mitogenic agent in the human prostate gland acting by autocrine/paracrine mechanisms. Here we extend knowledge on the VIP system (expression of VIP and VIP receptors, functionality of VIP receptors) at this level by analyzing the differences between human normal prostate and prostate carcinoma specimens. RT-PCR showed the expression of mRNA for VIP in normal and malignant tissues, whereas VIP levels, as measured by enzyme immuno-analysis, were about two times higher in adenocarcinoma samples. Real-time RT-PCR indicated a minor expression of VPAC2 receptors in the prostate gland, as well as the overexpression of VPAC1 and PAC1 receptors in malignant tissue specimens. Radio-labeled binding experiments with [125I]VIP showed an increased number of VIP binding sites (2.5 times for the high- and 1.7 times for the low-affinity sites) during malignant transformation, whereas the affinity values were unaffected. The receptors were functional in control and cancer tissues as shown by the ability of increasing VIP doses to stimulate adenylate cyclase activity. Interestingly, JV-1-53 (a GHRH-related peptide analog) (at 0.1 microM) behaved as a potent VIP antagonist since it inhibited by 60% the maximal VIP effect upon the enzyme activity. The results further explain the mechanisms of the autocrine/paracrine actions of VIP in human prostate and prostatic carcinoma through the observation of differences between healthy tissue and malignant transformation. Moreover, present data support the potential usefulness of VIP and/or synthetic peptide analogs for diagnostic or radiotherapeutic purposes as well as for long-term peptide therapy in this malignancy.
Collado
Beatriz
B
Department of Biochemistry and Molecular Biology, University of Alcalá, Spain.
Carmena
María J
MJ
Sánchez-Chapado
Manuel
M
Ruíz-Villaespesa
Antonio
A
Bajo
Ana M
AM
Fernández-Martínez
Ana B
AB
Varga
Jozsef L
JL
Schally
Andrew V
AV
Prieto
Juan C
JC
D000368:Aged; D013007:Growth Hormone-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000737:chemistry* / Q000628:therapy; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface / Q000032:analysis; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D018005:Receptors, Vasoactive Intestinal Peptide / Q000032:analysis* / Q000235:genetics; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014660:Vasoactive Intestinal Peptide / Q000032:analysis* / Q000037:antagonists & inhibitors*
C495503:ADCYAP1R1 protein, human; C453742:JV 1-53; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D018005:Receptors, Vasoactive Intestinal Peptide; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; C495506:VIPR1 protein, human; C495509:VIPR2 protein, human; D014660:Vasoactive Intestinal Peptide; D013007:Growth Hormone-Releasing Hormone