Project description: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 ER stress-induction 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 endoplasmic reticulum (ER) stress. The formation of poly-ribosomes and ER swelling of treated cancer cells by electron microscopy 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.
