Dokument: In-vitro-Analyse des apoptosis-related protein-2: Stellenwert des Potentials und die Grenzen beim Zelltod von Melanomzellen

Titel:In-vitro-Analyse des apoptosis-related protein-2: Stellenwert des Potentials und die Grenzen beim Zelltod von Melanomzellen
Weiterer Titel:In vitro analysis of apoptosis-related protein-2: significance for its potential and limitation in melanoma cell death
URL für Lesezeichen:https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=49405
URN (NBN):urn:nbn:de:hbz:061-20190424-135300-2
Kollektion:Dissertationen
Sprache:Deutsch
Dokumententyp:Wissenschaftliche Abschlussarbeiten » Dissertation
Medientyp:Text
Autor: Ahmad, Mutmid [Autor]
Dateien:
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Dateien vom 23.04.2019 / geändert 23.04.2019
Beitragende:PD Dr. rer. nat. Santourlidis, Simeon [Gutachter]
Krieg, Andreas [Gutachter]
Stichwörter:Apoptose, Apoptosis-related protein-2, Melanom
Dewey Dezimal-Klassifikation:600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit
Beschreibungen:Metastasierende Tumore wie das maligne Melanom sind häufig mit einer erhöhten Resistenz gegenüber Apoptose verbunden, hervorgerufen durch verschiedene Ursachen. Daher ist der Erfolg einer systemischen Therapie des metastasierten Melanoms sehr gering.
Das Ziel der vorliegenden Arbeit besteht darin, das apoptosis-related protein (APR)-2 in vitro funktionell zu charakterisieren, welches als ein Mediator in der Apoptose dazu beiträgt, dass die Resistenz von Melanomzellen gegen konventionelle Chemotherapie überwunden wird. Jene molekularen Mechanismen werden identifiziert, in denen das genannte Protein Apoptose in Melanomzellen auslöst. Um dies zu erreichen, wurden die Melanomzelllinien A375 und BLM eingesetzt und das lentiviral vermittelte Tet-On- Expressiossystem angewandt, um die Expression des APR-2 Proteins zu regulieren. Die Generierung und Etablierung stabiler Klone (A375/TetOn-APR-2 und BLM/TetOn-APR-2) diente der funktionellen Analyse des apoptotischen Potentials des apoptosis-related protein (APR)-2. Dabei wurden verschiedene zellbiologische und molekularbiologische Techniken und Verfahren angewandt.
Eine regulierte Expression des APR-2 Proteins wurde als Auslöser des Zelltods von Melanomzellen durch einen apoptotischen Mechanismus entdeckt. Dieser apoptotische Mechanismus ist durch die Freisetzung von Cytochrom c, die Aktivierung von Caspase-3, Caspase-9 und die Spaltung von PARP charakterisiert. Außerdem zeigte die detaillierte funktionelle Analyse des APR-2-Proteins, dass die subzelluläre Lokalisation am endoplasmatischen Retikulum der Hauptakteur in der Modulation der APR-2-induzierten Apoptose von Melanomzellen ist. Es wurde festgestellt, dass die APR-2 induzierte Apoptose von Melanomzellen sowohl durch einen Stress des endoplasmatischen Retikulums als auch durch eine mitochondriale Dysregulation vermittelt wird. Der Stress des endoplasmatischen Retikulums ist charakterisiert durch die Erhöhung der intrazellulären Ca2+_ Freisetzung, die Aktivierung des inositol requiring enzyme 1α (IRE1α) und calpain sowie die Spaltung von Caspase-4. Die mitochondriale Dysregulation ist durch den Verlust des mitochondrialen Membranpotentials, die Spaltung von Caspase-9 und -3 und poly adenosine diphosphate ribose polymerase (PARP) gekennzeichnet. Ferner wurde die Aktivierung des apoptosis signal-regulating kinase (ASK) 1, c-jun-N-terminal kinase (JNK) und der Transkriptionsfaktoren AP-1 und p53 sowie die Induktion der Bax-Expression in APR-2-exprimierenden Zellen festgestellt. Die Analyse der subzellulären Lokalisation des APR-2-Proteins und des proapoptotischen Proteins Bax mittels Immunfluoreszenzfärbung und Western Blot ergab den Nachweis einer Lokalisation an den Mitochondrien und am ER. Indessen zeigten die Experimente mit spezifischen Inhibitoren und der siRNA drei Signalwege für die APR-2-induzierte Apoptose. Der erste Weg ist IRE1α / tumor necrosis factor receptor-associated factor 2 / ASK1 / JNK / Cyt.c / caspase- 9 / caspase-3 / PARP, der zweite umfasst calpain / caspase-4 / caspase-9 / caspase-3 / PARP. Der dritte Weg ist protein kinase RNA-like ER kinase / ATF4 / C/EBP homologous protein (CHOP) / Bim. Zusammenfassend zeigte die funktionelle Analyse von APR-2 seine Zuverlässigkeit als apoptotischer Mediator zur Überwindung der Melanomresistenz gegenüber Standardbehandlungen. Somit wird die Verwendung des APR-2 Gentransfers als ein alternativer Ansatz für die Melanombehandlung betrachtet.

Metastatic cancers such as melanoma are often associated with a growing resistance to apoptosis caused by different therapeutic modalities. However, the current systemic therapies of metastatic melanoma lead to minimal success.
The purpose of this work is to functionally characterize, in vitro, the ability of apoptosisrelated protein (APR)-2 as an apoptotic mediator to overcome melanoma resistance to conventional therapy and to address the underlying molecular mechanisms which lead to apoptosis of melanoma cells triggered by APR-2. Therefore, melanoma cell lines namely A375 and BLM were designed for a tightly regulated expression of APR-2 using lentiviral Tet-On expression system. The generation and establishment of stable clones (A375/TetOn-APR-2 and BLM/TetOn-APR-2) were performed in order to functionally analyze the apoptotic potential of APR-2 using different cell biological and molecular biological techniques and procedures.
The tightly regulated expression of APR-2 protein was found to trigger melanoma cell death by an apoptotic mechanism. This apoptotic mechanism consists of release of cytochrome c, followed by activation of caspase-9, caspase-3 followed by cleavage of PARP. In addition, the functional analysis of APR-2 protein, in detail, demonstrated that the subcellular localization of APR-2 to endoplasmic reticulum is the main actor in modulation of APR-2-induced apoptosis of melanoma cells. APR-2-induced apoptosis of melanoma cells was found to be mediated not only by mitochondrial dysregulation but also by endoplasmic reticulum (ER) stress. ER stress is marked by the intracellular increase of Ca2+ release leading to activation of both, inositol-requiring enzyme 1a (IRE1α) and calpain, which is followed by cleavage of caspase-4. While the mitochondrial dysregulation is characterized by the loss of mitochondrial membrane potential leading to release of cytochrome c, followed by activation of caspase-9, caspase-3 and poly adenosine diphosphate ribose polymerase (PARP). Further analysis of APR-2-induced apoptosis revealed its association with the activation of apoptosis signal-regulating kinase (ASK) 1, c-jun-N-terminal kinase (JNK), the transcription factors p53 and AP-1 leading to induction of Bax expression. The analysis of the subcellular localization of APR-2 and the proapoptotic protein Bax by the use of western blotting and immune fluorescence staining revealed the localization of APR-2 at ER whereas Bax protein was localized at both ER and mitochondria. However, due to the experiments with specific inhibitors and siRNAs three parallel pathways for the induction of apoptosis by APR-2 could be addressed: the first pathway includes IRE1α / TNF receptor associated factor 2 / ASK1 / JNK / Cyt. c / caspase-9 / caspase-3 / PARP; the second pathway includes calpain / caspase-4 / caspase-9 / caspase-3 / PARP; and the third pathway includes protein kinase RNA like ER kinase / ATF4 / C/EBP homologous protein (CHOP) / Bim. In conclusion, the functional analysis of APR-2 revealed its reliability as an apoptotic mediator to overcome melanoma resistance to standard treatments. Thus, the utilization of APR-2 gene transfer as an alternative approach for the melanoma treatment is considered.
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Urheberrechtsschutz
Bezug:2009 - 2019
Fachbereich / Einrichtung:Medizinische Fakultät » Institute » Institut für Transplantationsdiagnostik und Zelltherapeutika (ITZ)
Dokument erstellt am:24.04.2019
Dateien geändert am:24.04.2019
Promotionsantrag am:04.10.2018
Datum der Promotion:21.03.2019
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