Prodigiosin Sensitizes Sensitive and Resistant Urothelial Carcinoma Cells to Cisplatin Treatment
Lena Berning,
David Schlütermann,
Annabelle Friedrich,
Niklas Berleth,
Yadong Sun,
Wenxian Wu,
María José Mendiburo,
Jana Deitersen,
Hannah U. C. Brass,
Margaretha A. Skowron,
Michèle J. Hoffmann,
Günter Niegisch,
Jörg Pietruszka,
Björn Stork
Affiliations
Lena Berning
Institute of Molecular Medicine I, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany
David Schlütermann
Institute of Molecular Medicine I, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany
Annabelle Friedrich
Institute of Molecular Medicine I, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany
Niklas Berleth
Institute of Molecular Medicine I, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany
Yadong Sun
Institute of Molecular Medicine I, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany
Wenxian Wu
Institute of Molecular Medicine I, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany
María José Mendiburo
Institute of Molecular Medicine I, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany
Jana Deitersen
Institute of Molecular Medicine I, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany
Hannah U. C. Brass
Institute of Bioorganic Chemistry, Faculty of Mathematics and Natural Sciences, Heinrich Heine University, Forschungszentrum Jülich, Stetternicher Forst, 52428 Jülich, Germany
Margaretha A. Skowron
Department of Urology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany
Michèle J. Hoffmann
Department of Urology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany
Günter Niegisch
Department of Urology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany
Jörg Pietruszka
Institute of Bioorganic Chemistry, Faculty of Mathematics and Natural Sciences, Heinrich Heine University, Forschungszentrum Jülich, Stetternicher Forst, 52428 Jülich, Germany
Björn Stork
Institute of Molecular Medicine I, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany
Cisplatin-based treatment is the standard of care therapy for urothelial carcinomas. However, complex cisplatin resistance mechanisms limit the success of this approach. Both apoptosis and autophagy have been shown to contribute to this resistance. Prodigiosin, a secondary metabolite from various bacteria, exerts different biological activities including the modulation of these two cellular stress response pathways. We analyzed the effect of prodigiosin on protein levels of different autophagy- and apoptosis-related proteins in cisplatin-sensitive and -resistant urothelial carcinoma cells (UCCs). Furthermore, we investigated the effect on cell viability of prodigiosin alone or in combination with cisplatin. We made use of four different pairs of cisplatin-sensitive and -resistant UCCs. We found that prodigiosin blocked autophagy in UCCs and re-sensitized cisplatin-resistant cells to apoptotic cell death. Furthermore, we found that prodigiosin is a potent anticancer agent with nanomolar IC50 values in all tested UCCs. In combination studies, we observed that prodigiosin sensitized both cisplatin-sensitive and -resistant urothelial carcinoma cell lines to cisplatin treatment with synergistic effects in most tested cell lines. These effects of prodigiosin are at least partially mediated by altering lysosomal function, since we detected reduced activities of cathepsin B and L. We propose that prodigiosin is a promising candidate for the therapy of cisplatin-resistant urothelial carcinomas, either as a single agent or in combinatory therapeutic approaches.
