<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Anti-Tumorigenic Effects of the Iron Chelator Ciclopirox in HPV-Positive Cancer Cells"^^ . "Oncogenic human papillomaviruses (HPVs) account for 5% of the total cancer incidence, being causal agents of cervical, other anogenital and oropharyngeal cancers. Innovative treatment options for HPV-induced cancers are thus urgently required. Metabolic alterations constitute one of the hallmarks of cancer, suggesting metabolic modulators such as iron chelators as a promising strategy for cancer therapy. In line with this, the iron chelating antifungal drug ciclopirox (CPX) showed promising anti-tumorigenic effects in numerous preclinical tumor models, including cervical cancer cells. In HPV-positive tumor cells, CPX suppresses expression of the viral E6/E7 oncogenes and induces senescence or apoptosis. This thesis aimed to delineate the mechanisms underlying these anti-tumorigenic effects in cervical cancer cells and more specifically to gain insights into the determinants governing the switch from senescence to apoptosis. \r\nBy analyzing data from a comprehensive proteome screen of CPX-treated HPV16-positive tumor cells potential pathways involved in its anti-tumorigenic capacity were identified, including the induction of tumor-suppressive Notch signaling and deregulation of the cellular energy metabolism. The latter effect could be corroborated by demonstrating that CPX represses factors involved in oxidative phosphorylation (OXPHOS), accompanied by an upregulation of glycolysis related proteins. Consequently, the anti-tumorigenic effects of CPX were strongly glucose-dependent in that limited glucose availability facilitated the induction of apoptosis, while increased glucose supply prevented CPX-mediated cell death – a regulation shared by established OXPHOS inhibitors such as the anti-diabetic drug metformin. Instead, under glucose-replete conditions CPX-treated cells underwent senescence, which was not observed for metformin and other OXPHOS inhibitors, but for other iron chelators. Moreover, it was shown that viral E6/E7 repression by CPX, metformin and other OXPHOS inhibitors is prevented by increasing glucose supply, indicating a vulnerability of HPV-oncogene expression to energy depletion. Additionally, experiments in E6/E7 expressing normal keratinocytes point towards a sensitizing role of the viral oncogenes towards CPX-treatment. Finally, it was demonstrated that CPX synergistically enhances the growth-suppressing effects of radiotherapy, cisplatin and glycolysis inhibitors in HPV-positive cancer cells.\r\nCollectively, the present study reveals a profound glucose-dependence of the anti-tumorigenic effects exerted by CPX and links its capacity to induce senescence or apoptosis to its dual role as an iron chelator and OXPHOS inhibitor, respectively. These results provide novel insights into the regulation of critical tumor-suppressive pathways in cervical cancer cells, illuminate the anti-proliferative activities of CPX and may facilitate the development of rational combination therapies comprised of CPX and glycolytic inhibitors to induce metabolic synthetic lethality in HPV-positive tumor cells."^^ . "2021" . . . . . . . "Anja Lena"^^ . "Herrmann"^^ . "Anja Lena Herrmann"^^ . . . . . . "Anti-Tumorigenic Effects of the Iron Chelator Ciclopirox in HPV-Positive Cancer Cells (PDF)"^^ . . . "Dissertation_Anja_Herrmann_PDFA.pdf"^^ . . . "Anti-Tumorigenic Effects of the Iron Chelator Ciclopirox in HPV-Positive Cancer Cells (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Anti-Tumorigenic Effects of the Iron Chelator Ciclopirox in HPV-Positive Cancer Cells (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Anti-Tumorigenic Effects of the Iron Chelator Ciclopirox in HPV-Positive Cancer Cells (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Anti-Tumorigenic Effects of the Iron Chelator Ciclopirox in HPV-Positive Cancer Cells (Other)"^^ . . . . . . "small.jpg"^^ . . . "Anti-Tumorigenic Effects of the Iron Chelator Ciclopirox in HPV-Positive Cancer Cells (Other)"^^ . . . . . . "indexcodes.txt"^^ . . "HTML Summary of #30927 \n\nAnti-Tumorigenic Effects of the Iron Chelator Ciclopirox in HPV-Positive Cancer Cells\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .