Regulation of eIF4F Translation Initiation Complex by the Peptidyl Prolyl Isomerase FKBP7 in Taxane-resistant Prostate Cancer

Purpose: Targeted therapies that use the signaling path-characterize the function of human FKBP7 and explore its ways involved in prostate cancer are required to overcome role in cancer. We discovered that FKBP7 was upregulated chemoresistance and improve treatment outcomes for men. in human prostate cancers and its expression correlated Molecular chaperones play a key role in the regulation of with the recurrence observed in patients receiving doce-protein homeostasis and are potential targets for overcom-taxel. FKBP7 silencing showed that FKBP7 is required to ing chemoresistance. maintain the growth of chemoresistant cell lines and Experimental Design: We established 4 chemoresistant chemoresistant tumors in mice. Mass spectrometry analysis prostate cancer cell lines and used image-based high-content revealed that FKBP7 interacts with eIF4G, a component of siRNA functional screening, based on gene-expression signa-the eIF4F translation initiation complex, to mediate the ture, to explore mechanisms of chemoresistance and identify survival of chemoresistant cells. Using small-molecule new potential targets with potential roles in taxane resistance. inhibitors of eIF4A, the RNA helicase component of The functional role of a new target was assessed by in vitro and eIF4F, we were able to kill docetaxel- and cabazitaxel-in vivo silencing, and mass spectrometry analysis was used to resistant cells. identify its downstream effectors. Conclusions: Targeting FKBP7 or the eIF4G-containing Results: We identified FKBP7, a prolyl-peptidyl isomer-eIF4F translation initiation complex could be novel thera-ase overexpressed in docetaxel-resistant and in cabazitaxel-peutic strategies to eradicate taxane-resistant prostate cancer resistant prostate cancer cells. This is the first study to cells.