Angiostatin generation by cathepsin D secreted by human prostate carcinoma cells

Wataru Morikawa, Kenji Yamamoto, Sara Ishikawa, Sumiyo Takemoto, Mayumi Ono, Jun Ichi Fukushi, Seiji Naito, Chikateru Nozaki, Sadaaki Iwanaga, Michihiko Kuwano

Research output: Contribution to journalArticle

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Abstract

Angiostatin, a potent endogenous inhibitor of angiogenesis, is generated by cancer-mediated proteolysis of plasminogen. The culture medium of human prostate carcinoma cells, when incubated with plasminogen at a variety of pH values, generated angiostatic peptides and miniplasminogen. The enzyme(s) responsible for this reaction was purified and identified as procathepsin D. The purified procathepsin D, as well as cathepsin D, generated two angiostatic peptides having the same NH2-terminal amino acid sequences and comprising kringles 1-4 of plasminogen in the pH range of 3.0-6.8, most strongly at pH 4.0 in vitro. This reaction required the concomitant conversion of procathepsin D to catalytically active pseudocathepsin D. The conversion of pseudocathepsin D to the mature cathepsin D was not observed by the prolonged incubation. The affinity-purified angiostatic peptides inhibited angiogenesis both in vitro and in vivo. Importantly, procathepsin D secreted by human breast carcinoma cells showed a significantly lower angiostatin-generating activity than that by human prostate carcinoma cells. Since deglycosylated procathepsin D from both prostate and breast carcinoma cells exhibited a similar low angiostatin-generating activity, this discrepancy appeared to be attributed to the difference in carbohydrate structures of procathepsin D molecules between the two cell types. The seminal vesicle fluid from patients with prostate carcinoma contained the mature cathepsin D and procathepsin D, but not pseudocathepsin D, suggesting that pseudocathepsin D is not a normal intermediate of procathepsin D processing in vivo. The present study provides evidence for the first time that cathepsin D secreted by human prostate carcinoma cells is responsible for angiostatin generation, thereby causing the prevention of tumor growth and angiogenesis-dependent growth of metastases.

Original languageEnglish
Pages (from-to)38912-38920
Number of pages9
JournalJournal of Biological Chemistry
Volume275
Issue number49
DOIs
Publication statusPublished - Dec 8 2000

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Angiostatins
Cathepsin D
Prostate
Angiostatic Proteins
Cells
Carcinoma
Plasminogen
Kringles
Proteolysis
Breast Neoplasms
Angiogenesis Inhibitors
procathepsin D
Seminal Vesicles
Growth
Human Activities
Culture Media
Tumors
Amino Acid Sequence
Neoplasms
Carbohydrates

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Morikawa, W., Yamamoto, K., Ishikawa, S., Takemoto, S., Ono, M., Fukushi, J. I., ... Kuwano, M. (2000). Angiostatin generation by cathepsin D secreted by human prostate carcinoma cells. Journal of Biological Chemistry, 275(49), 38912-38920. https://doi.org/10.1074/jbc.M005402200

Angiostatin generation by cathepsin D secreted by human prostate carcinoma cells. / Morikawa, Wataru; Yamamoto, Kenji; Ishikawa, Sara; Takemoto, Sumiyo; Ono, Mayumi; Fukushi, Jun Ichi; Naito, Seiji; Nozaki, Chikateru; Iwanaga, Sadaaki; Kuwano, Michihiko.

In: Journal of Biological Chemistry, Vol. 275, No. 49, 08.12.2000, p. 38912-38920.

Research output: Contribution to journalArticle

Morikawa, W, Yamamoto, K, Ishikawa, S, Takemoto, S, Ono, M, Fukushi, JI, Naito, S, Nozaki, C, Iwanaga, S & Kuwano, M 2000, 'Angiostatin generation by cathepsin D secreted by human prostate carcinoma cells', Journal of Biological Chemistry, vol. 275, no. 49, pp. 38912-38920. https://doi.org/10.1074/jbc.M005402200
Morikawa W, Yamamoto K, Ishikawa S, Takemoto S, Ono M, Fukushi JI et al. Angiostatin generation by cathepsin D secreted by human prostate carcinoma cells. Journal of Biological Chemistry. 2000 Dec 8;275(49):38912-38920. https://doi.org/10.1074/jbc.M005402200
Morikawa, Wataru ; Yamamoto, Kenji ; Ishikawa, Sara ; Takemoto, Sumiyo ; Ono, Mayumi ; Fukushi, Jun Ichi ; Naito, Seiji ; Nozaki, Chikateru ; Iwanaga, Sadaaki ; Kuwano, Michihiko. / Angiostatin generation by cathepsin D secreted by human prostate carcinoma cells. In: Journal of Biological Chemistry. 2000 ; Vol. 275, No. 49. pp. 38912-38920.
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