Secretome and degradome profiling shows that Kallikrein-related peptidases 4, 5, 6, and 7 induce TGF尾-1 signaling in ovarian cancer cells
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- 作者：Hasmik Shahinian ; Daniela Loessner ; Martin L. Biniossek ; Jayach ; ran N. Kizhakkedathu ; Judith A. Clements ; Viktor Magdolen ; Oliver Schilling
- 关键词：Proteolysis ; Kallikrein-related proteases ; Ovarian cancer ; Degradomics ; Transforming growth factor beta
- 刊名：Molecular Oncology
- 出版年：February, 2014
- 年：2014
- 卷：8
- 期：1
- 页码：68-82
- 全文大小：2032 K
文摘
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 (鈥渟ecretome鈥? and proteolytic profile (鈥渄egradome鈥? 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 尾-1 (TGF尾-1). KLK4-7 co-transfected OV-MZ-6 cells share prominent features of elevated TGF尾-1 signaling, including increased abundance of neural cell adhesion molecule L1 (L1CAM). Augmented levels of TGF尾-1 and L1CAM upon expression of KLK4-7 were corroborated in聽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尾-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尾-1 signaling in tumor biology.