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Secretome and degradome profiling shows that Kallikrein-related peptidases 4, 5, 6, and 7 induce TGFβ-1 signaling in ovarian cancer cells.
Mol Oncol 2014; 8(1):68-82MO

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+Show Affiliations

Institute of Molecular Medicine and Cell Research, University of Freiburg, D-79104 Freiburg, Germany.Cancer Program, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Kelvin Grove, Brisbane, Queensland 4059, Australia.Institute of Molecular Medicine and Cell Research, University of Freiburg, D-79104 Freiburg, Germany.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.Cancer Program, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Kelvin Grove, Brisbane, Queensland 4059, Australia.Clinical Research Unit, Department of Obstetrics and Gynecology, Technical University of Munich, D-81675, Germany.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24120346

Citation

Shahinian, Hasmik, et al. "Secretome and Degradome Profiling Shows That Kallikrein-related Peptidases 4, 5, 6, and 7 Induce TGFβ-1 Signaling in Ovarian Cancer Cells." Molecular Oncology, vol. 8, no. 1, 2014, pp. 68-82.
Shahinian H, Loessner D, Biniossek ML, et al. Secretome and degradome profiling shows that Kallikrein-related peptidases 4, 5, 6, and 7 induce TGFβ-1 signaling in ovarian cancer cells. Mol Oncol. 2014;8(1):68-82.
Shahinian, H., Loessner, D., Biniossek, M. L., Kizhakkedathu, J. N., Clements, J. A., Magdolen, V., & Schilling, O. (2014). Secretome and degradome profiling shows that Kallikrein-related peptidases 4, 5, 6, and 7 induce TGFβ-1 signaling in ovarian cancer cells. Molecular Oncology, 8(1), pp. 68-82. doi:10.1016/j.molonc.2013.09.003.
Shahinian H, et al. Secretome and Degradome Profiling Shows That Kallikrein-related Peptidases 4, 5, 6, and 7 Induce TGFβ-1 Signaling in Ovarian Cancer Cells. Mol Oncol. 2014;8(1):68-82. PubMed PMID: 24120346.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Secretome and degradome profiling shows that Kallikrein-related peptidases 4, 5, 6, and 7 induce TGFβ-1 signaling in ovarian cancer cells. AU - Shahinian,Hasmik, AU - Loessner,Daniela, AU - Biniossek,Martin L, AU - Kizhakkedathu,Jayachandran N, AU - Clements,Judith A, AU - Magdolen,Viktor, AU - Schilling,Oliver, Y1 - 2013/10/01/ PY - 2013/06/20/received PY - 2013/09/04/revised PY - 2013/09/18/accepted PY - 2013/10/15/entrez PY - 2013/10/15/pubmed PY - 2014/9/23/medline KW - Degradomics KW - Kallikrein-related proteases KW - Ovarian cancer KW - Proteolysis KW - Transforming growth factor beta SP - 68 EP - 82 JF - Molecular oncology JO - Mol Oncol VL - 8 IS - 1 N2 - 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. SN - 1878-0261 UR - https://www.unboundmedicine.com/medline/citation/24120346/Secretome_and_degradome_profiling_shows_that_Kallikrein_related_peptidases_4_5_6_and_7_induce_TGFβ_1_signaling_in_ovarian_cancer_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1574-7891(13)00139-7 DB - PRIME DP - Unbound Medicine ER -