Abstract
Numerous studies investigated the localization of pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors in different tumors and described the effects of analogs on tumor growth to show its potential role in oncogenesis. Recently, our research group has found significantly lower levels of PACAP27-like immunorreactivity (LI) and PACAP38-LI in different human samples of primary small cell lung cancer and colon cancer compared to normal healthy tissues. There are only few human studies showing the presence of PACAP and its receptors in urogenital tumors; therefore, the aim of the present study was to compare PACAP-LI in different healthy and pathological human samples from urogenital organs (kidney, urinary bladder, prostate, testis) with radioimmunoassay (RIA) method. Similar to our earlier observations, the PACAP27-LI was significantly lower compared to PACAP38-LI in all samples. We did not find significant alterations in PACAP-LI between healthy and tumoral samples from the urinary bladder and testis. On the other hand, we found significantly lower PACAP38-LI level in kidney tumors compared with healthy tissue samples, and we showed higher PACAP27-LI in prostatic cancer compared to samples from benign prostatic hyperplasia. These data indicate that PACAP levels of different tissue samples are altered under pathological conditions suggesting a potential role of PACAP in the development of different urogenital tumors.
Similar content being viewed by others
References
Arimura A, Somogyvari-Vigh A, Miyata A, Mizuno K, Coy DH, Kitada C (1991) Tissue distribution of PACAP as determined by RIA: highly abundant in the rat brain and testes. Endocrinology 129:2787–2789
Arimura A, Li M, Batuman V (2006a) Potential protective action of pituitary adenylate cyclase-activating polypeptide (PACAP38) on in vitro and in vivo models of myeloma kidney injury. Blood 107:661–668
Arimura A, Li M, Batuman V (2006b) Treatment of renal failure associated with multiple myeloma and other diseases by PACAP-38. Ann N Y Acad Sci 1070:1–4
Arms L, Vizzard MA (2011) Neuropeptides in lower urinary tract function. Handb Exp Pharmacol 202:395–423
Banki E, Degrell P, Kiss P, Kovacs K, Kemeny A, Csanaky K, Duh A, Nagy D, Toth G, Tamas A, Reglodi D (2013) Effect of PACAP treatment on kidney morphology and cytokine expression in rat diabetic nephropathy. Peptides 42:125–130
Banki E, Kovacs K, Nagy D, Juhasz T, Degrell P, Csanaky K, Kiss P, Jancso G, Toth G, Tamas A, Reglodi D (2014) Molecular mechanisms underlying the nephroprotective effects of PACAP in diabetes. J Mol Neurosci 54:300–309
Borzsei R, Mark L, Tamas A, Bagoly T, Bay C, Csanaky K, Banki E, Kiss P, Vaczy A, Horvath G, Nemeth J, Szauer E, Helyes Z, Reglodi D (2009) Presence of pituitary adenylate cyclase activating polypeptide-38 in human plasma and milk. Eur J Endocrinol 160:561–565
Bossowska A, Crayton R, Radziszewski P, Kmiec Z, Majewski M (2009) Distribution and neurochemical characterization of sensory dorsal root ganglia neurons supplying porcine urinary bladder. J Physiol Pharmacol 60(Suppl 4):77–81
Brubel R, Boronkai A, Reglodi D, Racz B, Nemeth J, Kiss P, Lubics A, Toth G, Horvath G, Varga T, Szogyi D, Fonagy E, Farkas J, Barakonyi A, Bellyei S, Szereday L, Koppan M, Tamas A (2010) Changes in the expression of pituitary adenylate cyclase-activating polypeptide in the human placenta during pregnancy and its effects on the survival of JAR choriocarcinoma cells. J Mol Neurosci 42:450–458
Brubel R, Horvath G, Reglodi D, Lubics A, Tamas A, Kiss P, Laszlo E, Nemeth J, Mark L, Szakaly P (2011) Presence of pituitary adenylate cyclase activating polypeptide and its type I receptor in the rat kidney. Transplant Proc 43:1297–1299
Brubel R, Kiss P, Vincze A, Varga A, Varnagy A, Bodis J, Mark L, Jambor E, Maasz G, Hashimoto H, Helyes Z, Toth G, Tamas A, Koppan M, Reglodi D (2012) Effects of pituitary adenylate cyclase activating polypeptide on human sperm motility. J Mol Neurosci 48:623–630
Busto R, Carrero I, Guijarro LG, Solano RM, Zapatero J, Noguerales F, Prieto JC (1999) Expression, pharmacological, and functional evidence for PACAP/VIP receptors in human lung. Am J Physiol 277(1 Pt 1):L42–L48
Busto R, Prieto JC, Bodega G, Zapatero J, Carrero I (2000) Immunohistochemical localization and distribution of VIP/PACAP receptors in human lung. Peptides 21:265–269
Busto R, Prieto JC, Bodega G, Zapatero J, Fogue L, Carrero I (2003) VIP and PACAP receptors coupled to adenylyl cyclase in human lung cancer: a study in biopsy specimens. Peptides 24:429–436
Cohen JR, Resnick DZ, Niewiadomski P, Dong H, Liau LM, Waschek JA (2010) Pituitary adenylyl cyclase activating polypeptide inhibits gli1 gene expression and proliferation in primary medulloblastoma derived tumorsphere cultures. BMC Cancer 10:676
D’Amico AG, Scuderi S, Saccone S, Castorina A, Drago F, D’Agata V (2013) Antiproliferative effects of PACAP and VIP in serum-starved glioma cells. J Mol Neurosci 51:503–513
Dufes C, Alleaume C, Montoni A, Olivier JC, Muller JM (2003) Effects of the vasoactive intestinal peptide (VIP) and related peptides on glioblastoma cell growth in vitro. J Mol Neurosci 21:91–102
Fahrenkrug J, Hannibal J (1998) PACAP in visceral afferent nerves supplying the rat digestive and urinary tracts. Ann N Y Acad Sci 865:542–546
Garcia-Fernandez MO, Bodega G, Solano RM, Ruiz-Villaespesa A, Sanchez-Chapado M, Carmena MJ, Prieto JC (2002) Expression and distribution of pituitary adenylate cyclase-activating peptide in human prostate and prostate cancer tissues. Regul Pept 110:9–15
Garcia-Fernandez MO, Solano RM, Carmena MJ, Busto R, Bodega G, Ruiz-Villaespesa A, Prieto JC, Sanchez-Chapado M (2003) Expression of functional PACAP/VIP receptors in human prostate cancer and healthy tissue. Peptides 24:893–902
Gardiner SM, Rakhit T, Kemp PA, March JE, Bennett T (1994) Regional haemodynamic responses to pituitary adenylate cyclase activating polypeptide and vasoactive intestinal polypeptide in conscious rats. Br J Pharmacol 111:589–597
Germano PM, Lieu SN, Xue J, Cooke HJ, Christofi FL, Lu Y, Pisegna JR (2009) PACAP induces signaling and stimulation of 5-hydroxytryptamine release and growth in neuroendocrine tumor cells. J Mol Neurosci 39:391–401
Hannibal J, Fahrenkrug J (1995) Expression of pituitary adenylate cyclase activating polypeptide (PACAP) gene by rat spermatogenic cells. Regul Pept 55:111–115
Harmar AJ, Sheward WJ, Morrison CF, Waser B, Gugger M, Reubi JC (2004) Distribution of the VPAC2 receptor in peripheral tissues of the mouse. Endocrinology 145:1203–1210
Hatanaka M, Tanida M, Shintani N, Isojima Y, Kawaguchi C, Hashimoto H, Kakuda M, Haba R, Nagai K, Baba A (2008) Lack of light-induced elevation of renal sympathetic nerve activity and plasma corticosterone levels in PACAP-deficient mice. Neurosci Lett 444:153–156
Hautmann M, Friis UG, Desch M, Todorov V, Castrop H, Segerer F, Otto C, Schutz G, Schweda F (2007) Pituitary adenylate cyclase activating polypeptide stimulates renin secretion via activation of PAC1 receptors. J Am Soc Nephrol 18:1150–1156
Hong X, Huang L, Song Y (2008) Role of vasoactive intestinal peptide and pituitary adenylate cyclase activating polypeptide in the vaginal wall of women with stress urinary incontinence and pelvic organ prolapse. Int Urogynecol J Pelvic Floor Dysfunct 19:1151–1157
Horvath G, Mark L, Brubel R, Szakaly P, Racz B, Kiss P, Tamas A, Helyes Z, Lubics A, Hashimoto H, Baba A, Shintani S, Furjes G, Nemeth J, Reglodi D (2010a) Mice deficient in pituitary adenylate cyclase activating polypeptide display increased sensitivity to renal oxidative stress in vitro. Neurosci Lett 469:70–74
Horvath G, Racz B, Reglodi D, Kovacs K, Kiss P, Gallyas F Jr, Bognar Z, Szabo A, Magyarlaki T, Laszlo E, Lubics A, Tamas A, Toth G, Szakaly P (2010b) Effects of PACAP on mitochondrial apoptotic pathways and cytokine expression in rats subjected to renal ischemia–reperfusion. J Mol Neurosci 42:411–418
Horvath G, Brubel R, Kovacs K, Reglodi D, Opper B, Ferencz A, Szakaly P, Laszlo E, Hau L, Kiss P, Tamas A, Racz B (2011) Effects of PACAP on oxidative stress-induced cell death in primary rat kidney and human hepatocyte cell cultures. J Mol Neurosci 43:67–75
Ishizuka O, Alm P, Larsson B, Matthiason A, Andersson KE (1995) Facilitatory effect of pituitary adenylate cyclase activating polypeptide on micturition in normal, conscious rat. Neuroscience 66:1009–1014
Jakab B, Reglodi D, Jozsa R, Hollosy T, Tamas A, Lubics A, Lengvari I, Oroszi G, Szilvassy Z, Szolcsanyi J, Nemeth J (2004) Distribution of PACAP-38 in the central nervous system of various species determined by a novel radioimmunoassay. J Biochem Biophys Methods 61:189–198
Khan AM, Li M, Brant E, Maderdrut JL, Majid DS, Simon EE, Batuman V (2011) Renoprotection with pituitary adenylate cyclase-activating polypeptide in cyclosporine A-induced nephrotoxicity. J Investig Med 59:793–802
Lacombe A, Lelievre V, Roselli CE, Salameh W, Lue YH, Lawson G, Muller JM, Waschek JA, Vilain E (2006) Delayed testicular aging in pituitary adenylate cyclase-activating peptide (PACAP) null mice. Proc Natl Acad Sci U S A 103:3793–3798
Lam HC, Takahashi K, Ghatei MA, Kanse SM, Polak JM, Bloom SR (1990) Binding sites of a novel neuropeptide pituitary adenylate cyclase activating polypeptide in the rat brain and lung. Eur J Biochem 193:725–729
Le SV, Yamaguchi DJ, McArdle CA, Tachiki K, Pisegna JR, Germano P (2002) PAC1 and PACAP expression, signaling, and effect on the growth of HCT8, human colonic tumor cells. Regul Pept 109:115–125
Lee JH, Lee JY, Rho SB, Choi JS, Lee DG, An S, Oh T, Choi DC, Lee SH (2014) PACAP inhibits tumor growth and interferes with clusterin in cervical carcinomas. FEBS Lett 588:4730–4739
Leyton J, Coelho T, Coy DH, Jakowlew S, Birrer MJ, Moody TW (1998) PACAP(6–38) inhibits the growth of prostate cancer cells. Cancer Lett 125:131–139
Leyton J, Gozes Y, Pisegna J, Coy D, Purdom S, Casibang M, Zia F, Moody TW (1999) PACAP(6–38) is a PACAP receptor antagonist for breast cancer cells. Breast Cancer Res Treat 56:177–186
Li M, Arimura A (2003) Neuropeptides of the pituitary adenylate cyclase-activating polypeptide/vasoactive intestinal polypeptide/growth hormone-releasing hormone/secretin family in testis. Endocrine 20:201–214
Li M, Maderdrut JL, Lertora JJL, Batuman V (2007) Intravenous infusion of pituitary adenylate cyclase activating polypeptide (PACAP) in a patient with multiple myeloma and myeloma kidney: a case study. Peptides 28:1891–1895
Li M, Maderdrut JL, Lertora JJL, Arimura A, Batuman V (2008) Renoprotection by pituitary adenylate cyclase activating polypeptide in multiple myeloma and other kidney diseases. Regul Pept 145:24–32
Li M, Balamuthusamy S, Khan AM, Maderdrut JL, Simon EE, Batuman V (2011) Pituitary adenylate cyclase activating polypeptide prevents cisplatin-induced renal failure. J Mol Neurosci 43:58–66
Mirabella N, Squillacioti C, Germano G, Varricchio E, Paino G (2001) Pituitary adenylate cyclase activating polypeptide (PACAP) immunoreactivity in the ureter of the duck. Cell Tissue Res 305:341–349
Miyata A, Jiang L, Dahl RD, Kitada C, Kubo K, Fujino M, Minamino N, Arimura A (1990) Isolation of a neuropeptide corresponding to the N-terminal 27 residues of the pituitary adenylate cyclase activating polypeptide with 38 residues (PACAP38). Biochem Biophys Res Commun 170:643–648
Moller K, Zhang YZ, Hakanson R, Luts A, Sjolund B, Uddman R, Sundler F (1993) Pituitary adenylate cyclase activating peptide is a sensory neuropeptide: immunocytochemical and immunochemical evidence. Neuroscience 57:725–732
Moody TW, Zia F, Makheja A (1993) Pituitary adenylate cyclase activating polypeptide receptors are present on small cell lung cancer cells. Peptides 14:241–246
Moody TW, Leyton J, Casibang M, Pisegna J, Jensen RT (2002) PACAP-27 tyrosine phosphorylates mitogen activated protein kinase and increases VEGF mRNAs in human lung cancer cells. Regul Pept 109:135–140
Moody TW, Chan D, Fahrenkrug J, Jensen RT (2003) Neuropeptides as autocrine growth factors in cancer cells. Curr Pharm Des 9:495–509
Moody TW, Osefo N, Nuche-Berenguer B, Ridnour L, Wink D, Jensen RT (2012) Pituitary adenylate cyclase activating polypeptide causes tyrosine phosphorylation on the EGF receptor in lung cancer cells. J Pharmacol Exp Ther 341:873–881
Nakamachi T, Sugiyama K, Watanabe J, Imai N, Kagami N, Hori M, Arat S, Shioda S (2014) Comparison of expression and proliferative effect of pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors on human astrocytoma cell lines. J Mol Neurosci 54:388–394
Nakamura K, Nakamachi T, Endo K, Ito K, Machida T, Oka T, Hori M, Ishizaka K, Shioda S (2014) Distribution of pituitary adenylate cyclase-activating polypeptide (PACAP) in the human testis and in testicular germ cell tumors. Andrologia 46:465–471
Nemeth J, Jakab B, Jozsa R, Hollosy T, Tamas A, Lubics A, Lengvari I, Kiss P, Oberritter Z, Horvath B, Szilvassy Z, Reglodi D (2007) PACAP-27 radioimmunoassay: description and application of a novel method. J Radioanal Nucl Chem 273:327–332
Olsson C, Holmgren S (1994) Distribution of PACAP (pituitary adenylate cyclase-activating polypeptide)-like and helospectin-like peptides in the teleost gut. Cell Tissue Res 277:539–547
Peeters K, Gerets HH, Princen K, Vandesande F (1999) Molecular cloning and expression of a chicken pituitary adenylate cyclase activating polypeptide receptor. Mol Brain Res 71:244–255
Reglodi D, Kiss P, Horvath G, Lubics A, Laszlo E, Tamas A, Racz B, Szakaly P (2012) Effects of pituitary adenylate cyclase activating polypeptide in the urinary system, with special emphasis on its protective effects in the kidney. Neuropeptides 46:61–70
Reubi JC (2000) In vitro evaluation of VIP/PACAP receptors in healthy and diseased human tissues. Clinical implications. Ann N Y Acad Sci 921:1–25
Reubi JC, Laderach U, Waser B, Gebbers JO, Robberecht P, Laissue JA (2000) Vasoactive intestinal peptide/pituitary adenylate cyclase-activating peptide receptor subtypes in human tumors and their tissues of origin. Cancer Res 60:3105–3112
Schafer H, Zheng J, Gundlach F, Günther R, Schmidt WE (1996) PACAP stimulates transcription of c-Fos and c-Jun and activates the AP-1 transcription factor in rat pancreatic carcinoma cells. Biochem Biophys Res Commun 221:111–116
Sherwood NM, Krueckl SL, McRory JE (2000) The origin and function of the pituitary adenylate cyclase activating polypeptide (PACAP)/glucagon superfamily. Endocr Rev 21:619–670
Shioda S, Nakajo S, Nakai Y, Arimura A (1998) Pituitary adenylate cyclase-activating polypeptide: a key player in male reproduction? Ann N Y Acad Sci 839:524–525
Sokolowska P, Nowak JZ (2008) Effects of PACAP and VIP on cAMP-generating system and proliferation of C6 glioma cells. J Mol Neurosci 36:286–291
Solano RM, Carmena MJ, Carrero I, Cavallaro S, Roman F, Hueso C, Travali S, Lopez-Fraile N, Guijarro LG, Prieto JC (1996) Characterization of vasoactive intestinal peptide/pituitary adenylate cyclase-activating peptide receptors in human benign hyperplastic prostate. Endocrinology 137:2815–2822
Solano RM, Carmena MJ, Busto R, Sánchez-Chapado M, Guijarro LG, Prieto JC (1999) Identification and functional properties of the pituitary adenylate cyclase activating peptide (PAC1) receptor in human benign hyperplastic prostate. Cell Signal 11:813–819
Szakaly P, Kiss P, Lubics A, Magyarlaki T, Tamas A, Racz B, Lengvari I, Toth G, Reglodi D (2008) Effects of PACAP on survival and renal morphology in rats subjected to renal ischemia-reperfusion. J Mol Neurosci 36:89–96
Szakaly P, Horvath G, Kiss P, Laszlo E, Farkas J, Furjes G, Nemeth J, Reglodi D (2010) Changes in pituitary adenylate cyclase-activating polypeptide following renal ischemia-reperfusion in rats. Transplant Proc 42:2283–2286
Szanto Z, Sarszegi Z, Reglodi D, Nemeth J, Szabadfi K, Kiss P, Varga A, Banki E, Csanaky K, Gaszner B, Pinter O, Szalai Z, Tamas A (2012) PACAP immunoreactivity in human malignant tumor samples and cardiac diseases. J Mol Neurosci 48:667–673
Vacas E, Fernandez-Martinez AB, Bajo AM, Sanchez-Chapado M, Schally AV, Prieto JC, Carmena MJ (2012) Vasoactive intestinal peptide (VIP) inhibits human renal cell carcinoma proliferation. Biochim Biophys Acta 1823:1676–1685
Vaudry D, Falluel-Morel A, Bourgault S, Basille M, Burel D, Wurtz O, Fournier A, Chow BK, Hashimoto H, Galas L, Vaudry H (2009) Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery. Pharmacol Rev 61:283–357
Yoshiyama M, de Groat WC (2008) The role of vasoactive intestinal polypeptide and pituitary adenylate cyclase activating polypeptide in the neural pathways controlling the lower urinary tract. J Mol Neurosci 36:227–240
Zia F, Fagarasan M, Bitar K, Coy DH, Pisegna JR, Wank SA, Moody TW (1995) Pituitary adenylate cyclase activating peptide receptors regulate the growth of non-small cell lung cancer cells. Cancer Res 55:4886–4891
Acknowledgments
This study was supported by the following grants: OTKA K104984, Arimura Foundation, TÁMOP-4.1.1.C-13/1/KONV-2014-0001, TÁMOP-4.2.2.B-15/KONV-2015-0011, TÁMOP 4.2.4.A/2-11-1-2012-0001 “National Excellence Program,” Janos Bolyai Research Scholarship of Hungarian Academy of Sciences, MTA-PTE “Lendulet” Program. The authors also thank all the volunteers.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Tamas, A., Javorhazy, A., Reglodi, D. et al. Examination of PACAP-Like Immunoreactivity in Urogenital Tumor Samples. J Mol Neurosci 59, 177–183 (2016). https://doi.org/10.1007/s12031-015-0652-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-015-0652-0