| RRC ID |
43177
|
| Author |
Kawakubo T, Okamoto K, Iwata J, Shin M, Okamoto Y, Yasukochi A, Nakayama KI, Kadowaki T, Tsukuba T, Yamamoto K.
|
| Title |
Cathepsin E prevents tumor growth and metastasis by catalyzing the proteolytic release of soluble TRAIL from tumor cell surface.
|
| Journal |
Cancer Res
|
| Abstract |
The aspartic proteinase cathepsin E is expressed predominantly in cells of the immune system and highly secreted by activated phagocytes, and deficiency of cathepsin E in mice results in a phenotype affecting immune responses. However, because physiologic substrates for cathepsin E have not yet been identified, the relevance of these observations to the physiologic functions of this protein remains speculative. Here, we show that cathepsin E specifically induces growth arrest and apoptosis in human prostate carcinoma tumor cell lines without affecting normal cells by catalyzing the proteolytic release of soluble tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) from the cell surface. The antitumor activity of cathepsin E was corroborated by in vivo studies with mice bearing human and mouse tumor transplants. Administration of purified cathepsin E into human tumor xenografts in nude mice dose-dependently induced apoptosis in the tumor cells to inhibit tumor growth. The growth, viability, and metastasis of mouse B16 melanoma cells were also more profound in cathepsin E-deficient mice compared with those in the syngeneic wild-type and transgenic mice overexpressing cathepsin E. Taken together, the number of apoptotic tumor cells, as well as tumor-infiltrating activated macrophages, was apparently reduced in cathepsin E-deficient mice compared with those in the other two groups, implying the positive correlation of endogenous cathepsin E levels with the extent of tumor suppression in vivo. These results thus indicate that cathepsin E plays a substantial role in host defense against tumor cells through TRAIL-dependent apoptosis and/or tumor-associated macrophage-mediated cytotoxicity.
|
| Volume |
67(22)
|
| Pages |
10869-78
|
| Published |
2007-11-15
|
| DOI |
10.1158/0008-5472.CAN-07-2048
|
| PII |
67/22/10869
|
| PMID |
18006832
|
| MeSH |
Animals
Apoptosis
Carcinoma / metabolism
Cathepsin E / metabolism*
Cell Membrane / metabolism*
Humans
Immune System
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Models, Biological
Neoplasm Metastasis
Neoplasms / metabolism*
Prostatic Neoplasms / metabolism
TNF-Related Apoptosis-Inducing Ligand / metabolism*
|
| IF |
9.727
|
| Times Cited |
62
|
|
WOS Category
|
ONCOLOGY
|
| Resource |
| Human and Animal Cells |
B16 melanoma |
