Desmocollin-3 Is a Novel Target Receptor for Targeted Drug Delivery for Malignant Prostate Cancer

Background: Malignant prostate cancer (PrC) remains challenging to treat due to tumor heterogeneity and the limited availability of ligands that target disease-associated surface markers with properties appropriate for targeted drug delivery systems. To overcome this hurdle, we used an unbiased but stringent selection strategy to discover a series of phage-displayed peptides that internalize specifically into PrC tumors. Methods: Here we report the characteristics, properties and function of one of these peptides, Pr10, and validate its ability to specifically deliver cytotoxic drugs into PrC cells and kill them, both in vitro and in xenograft models. Results: Biochemical and proteomic studies identified the receptor for Pr10 as Desmocollin-3 (DSC3). This finding was confirmed by demonstrating the expression of the DSC-3 protein on PrC cells; by siRNA knockdown of DSC3 expression, which abrogated Pr10 function; and by in silico docking experiments. Conclusions: Together, these findings identify DSC3 as a novel, functional receptor on malignant prostate cancer cells and establish Pr10 as an effective and PrC-selective ligand for drug delivery PrC cells. More broadly, this work highlights the ability of unbiased screening approaches to identify and isolate novel target receptors with properties appropriate for use in effective target drug delivery systems for cancer therapy.