期刊
MOLECULAR ONCOLOGY
卷 8, 期 1, 页码 68-82出版社
WILEY
DOI: 10.1016/j.molonc.2013.09.003
关键词
Proteolysis; Kallikrein-related proteases; Ovarian cancer; Degradomics; Transforming growth factor beta
类别
资金
- Deutsche Forschungsgemeinschaft (DFG) [SCHI 871/2]
- European Research Council [ERC-2011-StG 282111-ProteaSys]
- Excellence Initiative of the German Federal and State Governments [EXC 294]
- Michael Smith Foundation for Health Research (MSFHR)
- National Health and Medical Research Council (NHMRC) of Australia [553045]
- Australian Research Council [DP110103890]
- Cancer Council Queensland [1034134]
- German Academic Exchange Service (DAAD)
- German Federal Ministry of Education and Research, Leading Edge Cluster m4
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 beta-1 (TGF beta-1). KLK4-7 co-transfected OV-MZ-6 cells share prominent features of elevated TGF beta-1 signaling, including increased abundance of neural cell adhesion molecule L1 (L1CAM), Augmented levels of TGF beta-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 beta-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 beta-1 signaling in tumor biology. (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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