title: Secretome and degradome profiling shows that Kallikrein-related peptidases 4, 5, 6, and 7 induce TGFβ-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 β-1 (TGFβ-1). KLK4-7 co-transfected OV-MZ-6 cells share prominent features of elevated TGFβ-1 signaling, including increased abundance of neural cell adhesion molecule L1 (L1CAM). Augmented levels of TGFβ-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 TGFβ-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 TGFβ-1 signaling in tumor biology.
authors.affiliation: Institute of Molecular Medicine and Cell Research, University of Freiburg, D-79104 Freiburg, Germany.
authors.forename: Hasmik
authors.initials: H
authors.lastname: Shahinian
authors.affiliation: Cancer Program, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Kelvin Grove, Brisbane, Queensland 4059, Australia.
authors.forename: Daniela
authors.initials: D
authors.lastname: Loessner
authors.affiliation: Institute of Molecular Medicine and Cell Research, University of Freiburg, D-79104 Freiburg, Germany.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Biniossek
authors.affiliation: Centre for Blood Research, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Department of Chemistry, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Jayachandran N
authors.initials: JN
authors.lastname: Kizhakkedathu
authors.affiliation: Cancer Program, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Kelvin Grove, Brisbane, Queensland 4059, Australia.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Clements
authors.affiliation: Clinical Research Unit, Department of Obstetrics and Gynecology, Technical University of Munich, D-81675, Germany.
authors.forename: Viktor
authors.initials: V
authors.lastname: Magdolen
authors.affiliation: Institute of Molecular Medicine and Cell Research, University of Freiburg, D-79104 Freiburg, Germany; BIOSS Centre for Biological Signaling Studies, University of Freiburg, D-79104 Freiburg, Germany. Electronic address: oliver.schilling@mol-med.uni-freiburg.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Schilling
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007610:Kallikreins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010053:Ovary / Q000378:metabolism / Q000473:pathology; D059748:Proteolysis; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D053773:Transforming Growth Factor beta1; D007610:Kallikreins
keywords: Degradomics; Kallikrein-related proteases; Ovarian cancer; Proteolysis; Transforming growth factor beta