Interaction with Ribosomal Proteins Accompanies Stress Induction of the Anticancer Metallodrug BOLD-100/KP1339 in the Endoplasmic Reticulum
- Author(s)
- Benjamin Neuditschko, Anton A. Legin, Dina Baier, Arno Schintlmeister, Siegfried Reipert, Michael Wagner, Bernhard K. Keppler, Walter Berger, Samuel M. Meier-Menches, Christopher Gerner
- Abstract
The ruthenium-based anticancer agent BOLD-100/KP1339 has shown promising results in several in vitro and in vivo tumour models as well as in early clinical trials. However, its mode of action remains to be fully elucidated. Recent evidence identified stress induction in the endoplasmic reticulum (ER) and concomitant down-modulation of HSPA5 (GRP78) as key drug effects. By exploiting the naturally formed adduct between BOLD-100 and human serum albumin as an immobilization strategy, we were able to perform target-profiling experiments that revealed the ribosomal proteins RPL10, RPL24, and the transcription factor GTF2I as potential interactors of this ruthenium(III) anticancer agent. Integrating these findings with proteomic profiling and transcriptomic experiments supported ribosomal disturbance and concomitant induction of ER stress. The formation of polyribosomes and ER swelling of treated cancer cells revealed by TEM validated this finding. Thus, the direct interaction of BOLD-100 with ribosomal proteins seems to accompany ER stress-induction and modulation of GRP78 in cancer cells.
- Organisation(s)
- Department of Inorganic Chemistry, Department of Microbiology and Ecosystem Science, Large-Instrument Facility for Environmental and Isotope Mass Spectrometry, Department of Analytical Chemistry, Mass Spectrometry Centre, Joint Metabolome Facility
- External organisation(s)
- Research Cluster Translational Cancer Therapy Research, Medizinische Universität Wien
- Journal
- Angewandte Chemie (International Edition)
- Volume
- 60
- Pages
- 5063-5068
- No. of pages
- 6
- ISSN
- 1433-7851
- DOI
- https://doi.org/10.1002/anie.202015962
- Publication date
- 03-2021
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 104003 Inorganic chemistry, 301904 Cancer research, 301207 Pharmaceutical chemistry
- Keywords
- ASJC Scopus subject areas
- General Chemistry, Catalysis
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/9287b527-d4bd-494e-b8bd-f1ffa0c18511