Secretome and degradome profiling shows that Kallikrein-related peptidases 4, 5, 6, and 7 induce TGF beta-1 signaling in ovarian cancer cells
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Kallikrein-related peptidases, in particular KLK4, 5, 6 and 7 (4e7), often have elevatedexpression levels in ovarian cancer. In OV-MZ-6 ovarian cancer cells, combined expressionof KLK4e7 reduces cell adhesion and increases cell invasion and resistance to paclitaxel.The present work investigates how KLK4e7 shape the secreted proteome (“secretome”)and proteolytic profile (“degradome”) of ovarian cancer cells. The secretome comparisonconsistently identified>900 proteins in three replicate analyses. Expression of KLK4e7 pre-dominantly affected the abundance of proteins involved in cellecell communication.Among others, this includes increased levels of transforming growth factorb-1 (TGFb-1).KLK4e7 co-transfected OV-MZ-6 cells share prominent features of elevated TGFb-1signaling, including increased abundance of neural cell adhesion molecule L1 (L1CAM).Augmented levels of TGFb-1 and L1CAM upon expression of KLK4e7 were corroboratedin vivoby an ovarian cancer xenograft model. The degradomic analysis showed thatKLK4e7 expression mostly affected cleavage sites C-terminal to arginine, correspondingto the preference of kallikreins 4, 5 and 6. Putative kallikrein substrates include chemo-kines, such as growth differentiation factor 15 (GDF 15) and macrophage migration inhib-itory factor (MIF). Proteolytic maturation of TGFb-1 was also elevated. KLK4e7 have apronounced, yet non-degrading impact on the secreted proteome, with a strong associa-tion between these proteases and TGFb-1 signaling in tumor biology.