Cathepsin E prevents tumor growth and metastasis by catalyzing the proteolytic release of soluble TRAIL from tumor cell surface

Tomoyo Kawakubo, Kuniaki Okamoto, Jun Ichi Iwata, Masashi Shin, Yoshiko Okamoto, Atsushi Yasukochi, Keiichi I. Nakayama, Tomoko Kadowaki, Takayuki Tsukuba, Kenji Yamamoto

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)10869-10878
Number of pages10
JournalCancer Research
Volume67
Issue number22
DOIs
Publication statusPublished - Nov 15 2007

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Cathepsin E
Neoplasm Metastasis
Growth
Neoplasms
Apoptosis
Macrophages
Aspartic Acid Proteases
Experimental Melanomas
Phagocytes
Tumor Cell Line
Heterografts
Nude Mice
Transgenic Mice

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Kawakubo, T., Okamoto, K., Iwata, J. I., Shin, M., Okamoto, Y., Yasukochi, A., ... Yamamoto, K. (2007). Cathepsin E prevents tumor growth and metastasis by catalyzing the proteolytic release of soluble TRAIL from tumor cell surface. Cancer Research, 67(22), 10869-10878. https://doi.org/10.1158/0008-5472.CAN-07-2048

Cathepsin E prevents tumor growth and metastasis by catalyzing the proteolytic release of soluble TRAIL from tumor cell surface. / Kawakubo, Tomoyo; Okamoto, Kuniaki; Iwata, Jun Ichi; Shin, Masashi; Okamoto, Yoshiko; Yasukochi, Atsushi; Nakayama, Keiichi I.; Kadowaki, Tomoko; Tsukuba, Takayuki; Yamamoto, Kenji.

In: Cancer Research, Vol. 67, No. 22, 15.11.2007, p. 10869-10878.

Research output: Contribution to journalArticle

Kawakubo, T, Okamoto, K, Iwata, JI, Shin, M, Okamoto, Y, Yasukochi, A, Nakayama, KI, Kadowaki, T, Tsukuba, T & Yamamoto, K 2007, 'Cathepsin E prevents tumor growth and metastasis by catalyzing the proteolytic release of soluble TRAIL from tumor cell surface', Cancer Research, vol. 67, no. 22, pp. 10869-10878. https://doi.org/10.1158/0008-5472.CAN-07-2048
Kawakubo, Tomoyo ; Okamoto, Kuniaki ; Iwata, Jun Ichi ; Shin, Masashi ; Okamoto, Yoshiko ; Yasukochi, Atsushi ; Nakayama, Keiichi I. ; Kadowaki, Tomoko ; Tsukuba, Takayuki ; Yamamoto, Kenji. / Cathepsin E prevents tumor growth and metastasis by catalyzing the proteolytic release of soluble TRAIL from tumor cell surface. In: Cancer Research. 2007 ; Vol. 67, No. 22. pp. 10869-10878.
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