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"Biological and structural analysis of truncated analogs of PACAP27." J Mol Neurosci 36(1-3): 260-269. Publikationsserver der Universitätsbibliothek Marburg Universitätsbibliothek Marburg PACAP-Rezeptoren Zusammenfassung Die pleiotropen Neuropeptide PACAP (pituitary adenylate cyclase activating peptide) und VIP (vasoactive intestinal polypeptide) sind Mitglieder der VIP/PACAP/Glucagon/Secretin-Superfamilie und wirken über G-Proteingekoppelte-Rezeptoren. PACAP wirkt auf den PAC1-Rezeptor und wie VIP auf VPAC1 und VPAC2. Der Nachweis pharmakologischer Wirkungen von Agonisten und Antagonisten der VIP-/PACAP-Familie auf Bronchialkarzinomzelllinien durch Terry Moody lieferte erste Evidenzen, dass Bronchialkarzinomzellen funktionelle VIP-/PACAP-Rezeptoren exprimieren. Allerdings wurde das differentielle PAC1-, VPAC1- und VPAC2-Rezeptorprofil von Bronchialkarzinomzellen bisher noch nicht entschlüsselt. Deshalb setzte sich die vorliegende Arbeit zum Ziel, die mRNAExpressionsprofile der PAC1-, VPAC1- und VPAC2-Rezeptoren inklusive der PAC1-Splicevarianten in der murinen kleinzelligen Lewis-lung-carcinoma-1-(LLC1)-Zelllinie und deren subkutanen und pulmonalen Transplantaten sowie in verschiedenen humanen kleinzelligen Bronchialkarzinomzelllinien und -karzinomen zu differenzieren. Darüber hinaus sollten die Funktionalität des PAC1-Rezeptors in der LLC1-Zelllinie und die Wirkung von PAC1-Agonisten auf die Proliferation bzw. Apoptoserate in der humanen kleinzelligen NCI-H82-BronchiallkarzinomZelllinie getestet werden. Ein weiteres Ziel war, die Expression der tumorrelevanten PAC1-Zielgene Stanniocalcin 1 und Stathmin 1 in der murinen und den humanen Zelllinien und im humanen kleinzelligen Bronchialkarzinom zu bestimmen und den Einfluss PAC1-spezifischer Liganden auf ihre Expression zu erfassen. Folgende wesentliche neue Erkenntnisse wurden erzielt. Es gelang, die RNA-Expressionsprofile von PAC1, VPAC1 und VPAC2 und aller bekannten PAC1-Splicevarianten in der murinen LLC1-Tumorzelllinie und ihren subkutanen und pulmonalen Transplantaten sowie im humanen kleinzelligen Bronchialkarzinom zu differenzieren. Zwei Gruppen humaner Zelllinien kleinzelliger Bronchialkarzinome mit reziproker Abundanz von PAC1 und PACAP mRNA wurden differenziert. In Gruppe 1 war PAC1 hoch exprimiert und PACAP nicht detektierbar, in Gruppe 2 war PAC1 niedrig und PACAP hoch exprimiert. Mithilfe einer FRET-(Förster Resonanz Energie Transfer)-Messung konnte eine funktionell relevante Aktivierung des PAC1-Rezeptors in LLC1-Zellen durch subnanomolare Konzentrationen von PACAP38 nachgewiesen werden, welche die Synthese von cAMP induzierte und zur Freisetzung von Ca 2+ führte. Während die PAC1-Rezeptoraktivierung in der murinen LLC1-Zelllinie zu einer mäßigen Reduktion der Proliferationsrate führte, resultierte eine PAC1-Rezeptoraktivierung in der humanen NCI-H82-Zelllinie nur in einer marginalen Änderung der Proliferationsrate ohne nachweisbare Änderung der durch CisPt induzierten Apoptoserate. Die PAC1-Liganden Maxadilan, PACAP38 und PACAP27 schienen in LLC1-Zellen eine Rückkopplungshemmung der Expression des PAC1-Rezeptors auf mRNA-Niveau zu verursachen. Die murine LLC1-Zelllinie und das murine pulmonale LLC1 -Transplantat wiesen mRNA-Koexpression des PAC1-Rezeptors und seiner putativen Zielgene Stanniocalcin 1 und Stathmin 1 auf. Hingegen war das mRNA Koexpressionsmuster von PAC1 und seinen putativen Zielgenen Stanniocalcin 1 und Stathmin 1 in humanen kleinzelligen Bronchialkarzinomzelllinien und kleinzelligen Bronchialkarzinomen heterogen. Eine eindeutige Regulation der Transkription der genannten Zielgene durch eine PAC1-Rezeptoraktivierung konnte weder für die murine noch für die humanen kleinzelligen Bronchialkarzinomzelllinie(n) nachgewiesen werden. Die Ergebnisse lassen folgende Schlussfolgerungen zu. Da PAC1 und seine putativen Zielgene Stathmin 1 und Stanniocalcin 1 in murinen und humanen Zelllinien kleinzelliger Bronchialkarzinome in der Regel stark exprimiert sind, eignen sie sich sowohl in der präklinischen als auch klinischen Forschung als Bio- bzw. Tumormarker. Zum einen bietet sich an, Maxadilan -PET-Liganden zu entwickeln und für die diagnostische bzw. prognostische Tumorbildgebung einzusetzen. Zum anderen könnten PAC1-Rezeptoren auf kleinzelligen Bronchialkarzinomzellen für „Drug-targeting“ genutzt werden. Angesichts heterogener Ko-Expressionsmuster von PAC1-Rezeptoren und seinen beiden putativen Zielgenen Stanniocalcin 1 und Stathmin 1 in humanen kleinzelligen Bronchialkarzinomzelllinien liegt es nahe, das jeweilige kombinatorische Expressionsprofil von PAC1, PACAP, Stanniocalcin 1 und Stathmin 1 in Tumorbiopsien, Metastasen und Blutproben als Biomarker zur diagnostischen und prognostischen Differenzierung der Malignität von Bronchialkarzinomen im 3 Patienten zu nutzen. Insgesamt offerieren die hier erzielten Ergebnisse einen Beitrag für neue translationale Ansätze in der personalisierten Krebsmedizin. Schlüsselworte: kleinzelliges Bronchialkarzinom, kleinzellige Bronchialkarzinomzelllinien, LLC1-Zelllinie, PACAP, PAC1, VPAC1, VPAC2, PAC1-Splicevarianten, Stanniocalcin 1, Stathmin 1, Genexpression, Maxadilan ppn:347857310 https://doi.org/10.17192/z2014.0597 ths Prof. Dr. Weihe Eberhard Weihe, Eberhard (Prof. Dr.) Summary The pleiotropic neuropeptides PACAP (pituitary adenylate cyclase activating peptide) and VIP (vasoactive intestinal polypeptide) are members of the VIP/PACAP/glucagon/secretin superfamily and function via G-protein coupled receptors. PACAP acts on the PAC1 receptor and like VIP on VPAC1 and VPAC2 receptors. Pharmacological effects of agonists and antagonists of the VIP-/PACAP-family on lung cancer cell lines shown by Terry Moody provided first evidence that lung cancer cell lines express functional VIP -/PACAP receptors. However the differential PAC1, VPAC1 and VPAC2 receptor profiles of lung cancer cells have not yet been deciphered. Therefore, it was the aim of this thesis to differentiate the mRNA expression profiles of PAC1 and its splice variants, as well as that of VPAC1 and VPAC2 in the murine small cell Lewis-lung carcinoma-1-(LLC1) cell line and its subcutaneous and pulmonary transplants as well as in different human small cell lung cancer cell lines and carcinomas. In addition, the functionality of the PAC1-receptor in the LLC1 cell line and the effect of PAC1 agonists on proliferation and apoptosis in the human small cell lung cancer cell line NCI-H82 should be tested. Another objective was to determine the expression of the tumor relevant PAC1 target genes stanniocalcin 1 und stathmin 1 in the murine and human cell lines and in human small cell lung cancer and to detect the influence of PAC1-specific ligands on their expression. The following major new findings were obtained. The expression profile of PAC1, VPAC1 a nd VPAC2 and all known PAC1 splice variants in the murine LLC1-tumor cell line and its subcutaneous and pulmonary transplants and human small cell lung cancer cell lines was successfully differentiated. Two groups of human cell lines of small cell lung cancer featuring reciprocal abundance of PAC1 and PACAP mRNA could be differentiated. In group 1, PAC1 showed high and PACAP not detectable mRNA expression levels while in group 2 PAC1 expression was low and that of PACAP high. Using a FRET (Förster resonance energy transfer) experimental setup a functionally relevant activation of the PAC1 receptor in LLC1 cells by subnanomolar concentrations of PACAP38 was detected, which induced the synthesis of cAMP and the release of Ca2+. While the PAC1 receptor activation in the murine LLC1 cell line resulted in a modest reduction of the proliferation rate, the PAC1 receptor activation in the human NCI-H82 cell line resulted only in a marginal change of the rate of proliferation without detectable change of the CisPt-induced apoptosis rate. The selective PAC1 ligand maxadilan, PACAP38 and PACAP27 seemed to cause a feedback inhibition of the expression of PAC1 receptor at the mRNA level in LLC1 cells. The murine LLC1-cell line and the murine pulmonary LLC1 graft exhibited mRNA coexpression of PAC1 receptor and its putative target genes stanniocalcin 1 und stathmin 1. In contrast, mRNA coexpression patterns of PAC1, stanniocalcin 1 und stathmin 1 were heterogeneous in human small cell lung cancer cell lines and small cell lu ng cancer biopsies. Neither in the murine nor in the human small cell lung cancer cell line(s) evidence for transcriptional regulation of these two PAC1 target genes could be obtained. The results imply the following conclusions. Because PAC1 and its putative target genes stanniocalcin 1 und stathmin 1 are generally highly expressed in murine and human small cell lung cancer cell lines are, they are suitable biomarkers and tumor markes in both preclinical and clinical cancer research. Thus, the development of maxadilan PET ligands for prognostic and prognostic tumor imaging is a new perspective. PAC1 receptors on small cell bronchial carcinoma could serve for "drug targeting". In the light of the heterogeneous coexpression patterns of PAC1 -receptors, stanniocalcin 1 und stathmin 1 in human small cell lung cancer cell lines, combinatorial expression profiling of PAC1, PACAP, stanniocalcin 1 and stathmin 1 in tumor biopsies, metastases and blood samples is a new biomarking approach for diagnostic and prognostic differentiation of malignancy of lung cancers and their metastases in the clinics and preclinical research. Overall, the results obtained here offer a contribution to new translational approaches in personalized cancer medicine. Keywords : small cell lung cancer , small-cell lung carcinoma cell lines, LLC1 cell line , PACAP, PAC1, VPAC1, VPAC2, PAC1 splice variants, stanniocalcin 1, stathmin 1, gene expression, maxadilan PACAP urn:nbn:de:hebis:04-z2014-05979 Anatomie und Zellbiologie 2014-07-09 opus:5682 https://archiv.ub.uni-marburg.de/diss/z2014/0597/cover.png None of the above, but in this section Kleinzelliges Bronchialkarzinom Life sciences Biowissenschaften, Biologie ADCYAP1R1 Medizin doctoralThesis PACAP-receptors The PAC1-agonists and PACAP-receptors in murine and human small cell lung cancer cell lines German ADCYAP1R1 2014-09-25 Vasoaktives intestinales Peptid 2014-09-25 monograph