| First Author | Gomez-Auli A | Year | 2021 |
| Journal | Cell Mol Life Sci | Volume | 78 |
| Issue | 2 | Pages | 733-755 |
| PubMed ID | 32385587 | Mgi Jnum | J:304150 |
| Mgi Id | MGI:6694357 | Doi | 10.1007/s00018-020-03528-5 |
| Citation | Gomez-Auli A, et al. (2021) The secreted inhibitor of invasive cell growth CREG1 is negatively regulated by cathepsin proteases. Cell Mol Life Sci 78(2):733-755 |
| abstractText | Previous clinical and experimental evidence strongly supports a breast cancer-promoting function of the lysosomal protease cathepsin B. However, the cathepsin B-dependent molecular pathways are not completely understood. Here, we studied the cathepsin-mediated secretome changes in the context of the MMTV-PyMT breast cancer mouse model. Employing the cell-conditioned media from tumor-macrophage co-cultures, as well as tumor interstitial fluid obtained by a novel strategy from PyMT mice with differential cathepsin B expression, we identified an important proteolytic and lysosomal signature, highlighting the importance of this organelle and these enzymes in the tumor micro-environment. The Cellular Repressor of E1A Stimulated Genes 1 (CREG1), a secreted endolysosomal glycoprotein, displayed reduced abundance upon over-expression of cathepsin B as well as increased abundance upon cathepsin B deletion or inhibition. Moreover, it was cleaved by cathepsin B in vitro. CREG1 reportedly could act as tumor suppressor. We show that treatment of PyMT tumor cells with recombinant CREG1 reduced proliferation, migration, and invasion; whereas, the opposite was observed with reduced CREG1 expression. This was further validated in vivo by orthotopic transplantation. Our study highlights CREG1 as a key player in tumor-stroma interaction and suggests that cathepsin B sustains malignant cell behavior by reducing the levels of the growth suppressor CREG1 in the tumor microenvironment. |
