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Paula Lindner: Targeted cancer therapy – understanding the cytotoxic effects of depleting crucial cellular Ca2+ stores

PhD defense, Tuesday, 9 June 2020. Paula Lindner.

Paula Lindner

During her studies, Paula Lindner investigated the mechanisms of how the naturally occurring plant compound thapsigargin kills isolated human cancer cells. In particular, Lindner focused on understanding the role played by endoplasmic reticulum (ER) calcium depletion, ER stress signaling, and autophagy. By doing this, Lindner and colleagues revealed several novel connections and mechanisms that were previously unrecognized. Thapsigargin inhibits the ER Ca2+ pump SERCA, thereby disturbing intracellular Ca2+ homeostasis, which in turn affects essential cellular processes and eventually drives the cancer cells toward cell death. The effects of thapsigargin are of particular interest since it is mother compound for prodrugs designed for cancer therapy. The prodrugs are targeted to the tumor site as an effect of cleavage by cancer-specific proteases, which releases active thapsigargin analogs within the tumor environment. Several such prodrug-derived thapsigargin analogs were included in Lindner’s study, and effects on SERCA inhibition, ER Ca2+ depletion, stress signaling, and cell death were compared.

The new research findings contribute to the understanding of how thapsigargin exerts cytotoxic effects in cancer cells and aids future therapeutic efforts with Tg-derived prodrugs.

The joint PhD degree was completed at the Centre for Molecular Medicine Norway (NCMM), Faculty of Medicine, University of Oslo and Department of Molecular Biology and Genetics – DANDRITE, Faculty of Natural Sciences, Aarhus University

This resumé was prepared by the PhD student.

Time: Tuesday, 9 June 2020 at 11.15
Place: The Trial Lecture and the PhD defence will be held online. For more information see here.
Title of PhD thesis: Role of endoplasmic reticulum Ca2+ depletion, the unfolded protein response, and autophagy in thapsigargin-induced cell death
Contact information: Paula Lindner, e-mail: p.m.lindner@ncmm.uio.no
Members of the assessment committee:
Associate Professor Kasper Rouschop, Department of radiotherapy, University of Maastricht, The Netherlands
Associate Professor Ernst-Martin Füchtbauer, Department of Molecular Biology and Genetics, Aarhus University
Professor Marit Inngjerdingen, Institute of Clinical Medicine, Faculty of Medicine, UiO
Main supervisor:
Senior Scientist Nikolai Engedal, Centre for Molecular Medicine, Oslo University Hospital
Professor Poul Nissen, Department of Molecular Biology and Genetics, Aarhus University
Professor Anne Simonsen, Institute of Basic Medical Sciences, University of Oslo
Professor Emeritus Jesper Vuust Møller, Department of Biomedicine, Aarhus University
Language: The PhD dissertation will be defended in English

The defense is public.
Due to the coronavirus situation, Aarhus University is physically closed. Therefore, the PhD thesis will not be available for reading at the offices of the PhD administration. As the PhD thesis is defended through the University of Oslo because of the joint PhD degree cooperation, interested parties may instead see this page.