Einfluss der Bortezomib-induzierten p53-Reaktivierung auf die Strahlen- und Chemosensibilität HPV-assoziierter Plattenepithelkarzinome der Kopf-Hals-Region

Beim Plattenepithelkarzinom der Kopf-Hals-Region (HNSCC) hat sich die Einteilung in zwei ätiologisch verschiedene Subgruppen etabliert. Während Noxen-assoziierte HNSCC vorwiegend auf den Konsum von Tabak und Alkohol zurückzuführen sind, ist die Tumorprogression in mit Humanen Papillomaviren (HPV) as...

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Bibliographic Details
Main Author: Seltzsam, Steve
Contributors: Wittig, Andrea (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2018
Online Access:PDF Full Text
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Squamous cell carcinomas of the head and neck region (HNSCC) represent a frequent tumor entity that can be divided into two aetiologically different subgroups. While noxa-induced HNSCC are caused by tobacco and alcohol abuse, the carcinogenenis of Hu-man Papillomavirus (HPV) -associated HNSCC is driven by viral oncoproteins. Those HPV-positive HNSCC showed an impacting increase in incidence in the past years, especially in the oropharynx. Patients with HPV-positive HNSCC have a favorable prognosis caused by the tumor’s higher sensitivity towards cytostatics and irradiation. To date, the underlying mechanisms are only partly understood. One possible reason could be the impaired signaling pathway of the tumorsuppressor protein p53, that is – in contrast to noxa-associated HNSCC – expressed in wildtype form. In HPV-positive HNSCC, viral oncoproteins characteristically lead to a functional inhibition of the p53 pathway by accelerating its degradation by the proteasome. The aim of this work was to achieve a functional restoration of the p53 pathway and further impact on radio- and chemosensitivity by treatment with the proteasome inhibitor bortezomib in vitro. Therefore, cell viability, protein expression, cell-cycle progression, induction of apoptosis as well as clonogenic survival were obtained in four HPV-positive and three HPV-negative HNSCC cell lines after treatment with bortezomib, cisplatin and irradiation. As expected, a functional restoration of p53 with increase of downstream protein p21 expression by bortezomib was only achieved in HPV-positive cell strains and could be further enhanced by combining with irradiation. Concordant to that, a cell-cycle arrest in G1 phase and enhanced induction of apoptosis that could be explained by presence of restored p53 were observed only in HPV-positive cell strains. The clonogenic survival was impaired in all cell strains independently from HPV status. Furthermore, no radio- and chemosensitization were observed, neither in HPV-positive, nor in HPV-negative cell strains. The results show that the p53 signaling pathway is characteristically impaired in HPV-positive HNSCC cell lines and can thus be functionally restored by bortezomib treat-ment. The diverging results concerning clonogenic survival as well as the failed sensiti-zation towards standard therapeutics by bortezomib give evidence that probably other mechanisms apart from intact p53 might be responsible for the higher radio- and chemosensitivity of HPV-positive HNSCC.