Secretome and degradome profiling shows that Kallikrein-related peptidases 4, 5, 6, and 7 induce TGF?-1 signaling in ovarian cancer cells.

ABSTRACT: Kallikrein-related peptidases, in particular KLK4, 5, 6 and 7 (4-7), often have elevated expression levels in ovarian cancer. In OV-MZ-6 ovarian cancer cells, combined expression of KLK4-7 reduces cell adhesion and increases cell invasion and resistance to paclitaxel. The present work investigates how KLK4-7 shape the secreted proteome ("secretome") and proteolytic profile ("degradome") of ovarian cancer cells. The secretome comparison consistently identified >900 proteins in three replicate analyses. Expression of KLK4-7 predominantly affected the abundance of proteins involved in cell-cell communication. Among others, this includes increased levels of transforming growth factor ?-1 (TGF?-1). KLK4-7 co-transfected OV-MZ-6 cells share prominent features of elevated TGF?-1 signaling, including increased abundance of neural cell adhesion molecule L1 (L1CAM). Augmented levels of TGF?-1 and L1CAM upon expression of KLK4-7 were corroborated in vivo by an ovarian cancer xenograft model. The degradomic analysis showed that KLK4-7 expression mostly affected cleavage sites C-terminal to arginine, corresponding to the preference of kallikreins 4, 5 and 6. Putative kallikrein substrates include chemokines, such as growth differentiation factor 15 (GDF 15) and macrophage migration inhibitory factor (MIF). Proteolytic maturation of TGF?-1 was also elevated. KLK4-7 have a pronounced, yet non-degrading impact on the secreted proteome, with a strong association between these proteases and TGF?-1 signaling in tumor biology.

SUBMITTER: Shahinian H 

PROVIDER: S-EPMC5528505 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature