{Reference Type}: Journal Article
{Title}: Identification of mitochondrial ATP synthase as the cellular target of Ru-polypyridyl-β-carboline complexes by affinity-based protein profiling.
{Author}: Wang WJ;Ling YY;Shi Y;Wu XW;Su X;Li ZQ;Mao ZW;Tan CP;
{Journal}: Natl Sci Rev
{Volume}: 11
{Issue}: 8
{Year}: 2024 Aug
{Factor}: 23.178
{DOI}: 10.1093/nsr/nwae234
{Abstract}: Ruthenium polypyridyl complexes are promising anticancer candidates, while their cellular targets have rarely been identified, which limits their clinical application. Herein, we design a series of Ru(II) polypyridyl complexes containing bioactive β-carboline derivatives as ligands for anticancer evaluation, among which Ru5 shows suitable lipophilicity, high aqueous solubility, relatively high anticancer activity and cancer cell selectivity. The subsequent utilization of a photo-clickable probe, Ru5a, serves to validate the significance of ATP synthase as a crucial target for Ru5 through photoaffinity-based protein profiling. Ru5 accumulates in mitochondria, impairs mitochondrial functions and induces mitophagy and ferroptosis. Combined analysis of mitochondrial proteomics and RNA-sequencing shows that Ru5 significantly downregulates the expression of the chloride channel protein, and influences genes related to ferroptosis and epithelial-to-mesenchymal transition. Finally, we prove that Ru5 exhibits higher anticancer efficacy than cisplatin in vivo. We firstly identify the molecular targets of ruthenium polypyridyl complexes using a photo-click proteomic method coupled with a multiomics approach, which provides an innovative strategy to elucidate the anticancer mechanisms of metallo-anticancer candidates.